Cancer is a heterogeneous group of diseases presenting in various forms in various tissues but having in common the characteristic of uncontrolled cell proliferation. For some time, cancer has been recognized as a disease of uncontrolled cell proliferation. Thus, the rapidly proliferating cell has been the target of cancer chemotherapy. The goal is to find agents that are more effective against cancer cells than against normal cells. As the basic science of the cell progressed, it was shown that certain anticancer agents were more effective against malignant cells at certain stages of the cell cycle than against cells at other stages of the cell cycle.
Attempts were made to develop treatment regimens that took advantage of these observations (SHACKNEY, S. E. et al Cell Kinetics. IN: Bruce Chabner (ed.), Pharmacologic Principles of Cancer Treatment; W. B. Saunder Company: Philadelphia, pp. 45-76, (1982)). Cell replication is now recognized to be controlled by the transient, sequential, highly-regulated expression of a series of cyclins which associate with specific cyclin-dependent kinases (CDK""s) (TAULES, M., et al, J. Biol. Chem. 273, 33279-33286 (1998; FISHER, R. P. Current Opinion in Genetics and Develop. 7, 32-38 (1997); ARELLANO, M. et al., Int. J. Biochem. Cell Biol. 29, 559-573 (1997); and RAVITZ, M. J., et al. Adv. Cancer Res. 1997, 165-207 (1997)). These are serine/threonine protein kinases, which activate various enzymes and thereby initiate a cascade of phosphorylations allowing the cell to progress to the next stage of replication (COLLINS, et al., Proc. Natl. Acad. Sci. USA 94, 2776-2778 (1997); JACKS, T. et al., Science 280, 1035-1036 (1998)).
It has been found that cancerous cells often have mutated or missing components in the chain of proteins and enzymes, which control cell division. For example, the Rb protein, often called pRb, is a substrate for the cyclin-CDK""s and is frequently missing or mutated in human tumors (KONSTANTINIDIS, A. K. et al, J. Biol. Chem. 273, 26506-26515 (1998); HARRINGTON, E. A., et al., Proc. Natl. Acad. Sci. USA 95, 11945-11950 (1998); YAMAMOTO, et al., Oncol. Rep. 5, 447-451 (1997); BARTEK, J., et al., Exp. Cell Res. 237, 1-6 (1997); SELLERS, et al., J. Clin. Oncol. 15, 3301-3312 (1997); HERWIG, S. et al., Eur. J. Biochem. 246, 581-601 (1997)).
In addition to the kinases, which can help to move the cell from one phase of division to the next, there are CDK inhibitors (CKIs) that block the actions of specific cyclin-CDK complexes. The CKIs halt cell cycle progression and cause cells to enter the quiescent Go phase. The CKIs of the INK4 group, including p15, p16, p18, and p19, block the cyclin-CDK4 and cyclin-CDK6 complexes.
Calmodulin is essential for cyclin-dependent kinase 4 (CDK4) activity and nuclear accumulation of cyclin D1-CDK4 during the G1 phase (TAULES, M., et al, J. Biol. Chem. 273, 33279-33286 (1998)). CDKs and cyclins are important in transition(s) (FISHER, R. P. Current Opinion in Genetics and Develop. 7, 32-38 (1997)). CDK/cyclin complexes are regulated during the cell cycle (ARELLANO, M. et al., Int. J. Biochem. Cell Biol. 29, 559-573 (1997)). Cyclin-dependent kinase during the G1 phase, and the cell cycle generally are regulated by TGF-xcex2 (RAVITZ, M. J., et al. Adv. Cancer Res. 1997, 165-207 (1997)).
The most frequent alteration in human malignant disease thus far recognized is the overexpression, mutation, and/or disregulation of cyclin D (IMOTO, M., et al., Exp. Cell Res. 236, 173-180 (1997); JUAN, G., et al., Cell Prolif. 29, 259-266 (1996); GONG, J. et al., Cell Prolif. 28, 337-346 (1995) et al., 1995). The cyclin D1 gene, CCND1, is amplified in about 20% of breast cancers and the protein, cyclin D1, is overexpressed in about 50% of breast cancers (BARNES, D. M. et al., Breast Cancer Res. Treat. 52, 1-15 (1998); KAMALATI, T., et al., Clin. Exp. Metastasis 16, 415-426 (1998); STEEG, P. S. et al. Breast Cancer Res. Treat. 52, 17-28 (1998); LANDBERG, G. et al., APMIS 105, 575-589 (1997); ALLE, et al., Clin. Cancer Res. 4, 847-854 (1998)). Overexpression of cyclin D1 has been reported in proliferative breast disease and in ductal carcinoma in situ, indicating that this change is important at the earliest stages of breast oncogenesis (ALLE, et al., Clin. Cancer Res. 4, 847-854 (1998); STEEG, et al., Breast Cancer Res. Treat. 52, 17-28 (1998)).
One researcher (KAMALATI, T., et al., Clin. Exp. Metastasis 16, 415-426 (1998) et al. (1998)) treated normal human epithelial cells so that they overexpressed cyclin D1. These transfected cells had reduced growth factor dependency, a shortened cell cycle time, thus providing the cells with a growth advantage. In 123 colorectal carcinoma specimens, those staining strongly for cyclin D1 corresponded to patients with a 5-year survival rate of 53.3% while those that were negative or weakly staining had 5-year survival rates of 96.2 and 78.8% (MEEDA, K., et al., Oncology 55, 145-151 (1998); PALMQVIST, R., et al., Europ. J. Cancer 34, 1575-1581 (1998)).
Amplification of CCND1 was found in 25% of dysplastic head-and-neck lesions, and 22% of head-and-neck carcinomas. Overexpression of cyclin D1 was found in 53% of head-and-neck carcinomas. This indicates that in this disease, like breast cancer, alterations in cyclin D1 occur at the very earliest stages of tumorigenesis (KYOMOTO, R., et al., Int. J. Cancer (Pred. Oncol.) 74, 576-581 (1997); PIGNATARO, L., et al., J. Clin. Oncol. 16, 3069-3077 (1998) et al., 1998). In a study of 218 specimens of esophageal squamous cell carcinoma, patients with cyclin D1-positive tumors had significantly worse survival than patients with cyclin D1-negative tumors (SARBIA, M. et al., Int. J. Cancer (Pred. Oncol. 84, 86-91 (1999)).
In eight human esophageal carcinoma cell lines, 7 (87.5%) and 6 (75%) cell lines had homozygous deletions of the p16 and p15 genes (KITAHARA, K. et al., J. Exp. Therap. Oncol. 1, 7-12 (1996)). All of the p16-negative cell lines express high levels of cyclin D1 and CDK4.
The Rustgi laboratory (MUELLER, A, et al., Cancer Res. 57, 5542-5549 (1997); NAKAGAWA, H, et al., Oncogene 14, 1185-1190 (1997)) developed a transgenic mouse which the Epstein-Barr virus ED-L2 promoter was linked to human cyclin D1 cDNA. The transgene protein localizes to squamous epithelium in the tongue and esophagus, resulting in a dysplastic phenotype associated with increased cell proliferation and indicating that cyclin D1 overexpression may be a tumor-initiating event. In a series of 84 specimens of soft-tissue sarcomas, there was no amplification of the CCND1 gene but there was overexpression of cyclin D1 in 29% of cases. The overexpression of cyclin D1 was significantly associated with worse overall survival (KIM, S. H., et al., Clin. Cancer Res. 4, 2377-2382 (1998); YAO, J., et al., Clin. Cancer Res. 4, 1065-1070 (1998)).
Another researcher (MARCHETTI, A., et al., Int. J. Cancer 75, 187-192 (1998)) found that abnormalities of cyclin D1 and/or Rb at the gene and/or expression level were present in more than 90% of a series of non-small cell lung cancer specimens, indicating that cyclin D1 and/or Rb alterations represent an important step in lung tumorigenesis. In 49 out of 50 pancreatic carcinomas (98%), the Rb/p16 pathway was abrogated exclusively through inactivation of the p16 gene (SCHUTTE, M., et al., Cancer Res. 57, 3126-3130 (1997)).
Mantle cell lymphoma is defined as a subentity of malignant lymphomas characterized by the chromosomal translocation t(11;14)(q13;q32) resulting in overexpression of cyclin D1 and, in addition, about 50% of these tumors have deletion of the p16 gene (DREYLING, M. H., et al., Cancer Res. 57, 4608-4614 (1997); TANIGUCHI, T., et al., Jpn. J. Cancer Res. 89, 159-166 (1998)).
In a series of 17 hepatoblastomas, 76% showed overexpression of cyclin D1 and 88% showed overexpression of CDK4 (KIM, H., et al., Cancer Lett. 131, 177-183 (1998)). There was a correlation between high level cyclin D1 expression and tumor recurrence. Alterations in the cyclin D1/CDK4/pRb pathway have also been associated with a high percentage of prostate carcinomas (HAN, E. K. H., et al., The Prostate 35, 95-101 (1998)), ovarian carcinomas (MASCIULLO, V., et al., Int. J. Cancer Pred. Oncol. 74, 390-395 (1997)) and osteosarcomas (WEI, G., et al., Int. J. Cancer 80, 199-204 (1999) et al., 1999).
Six distinct classes of small molecules from natural products have been identified as inhibitors of CDKs: the purine-based compound olomoucine and analogs, butyrolactone, flavopiridol, staurosporine and UCN-01, suramin and 9-hydroxyellipticine (CARLSON et al., Cancer Res. 56, 2973-2978 (1996); DE AZEVEDO, et al., Eur. J. Biochem. 243, 518-526 (1997); BRIDGES, A. J. Exp. Opin. Ther. Patents 5, 1245-1257 (1995); ORR, M. S., et al., REINHOLD, W., et al., J. Biol. Chem. 278, 3803-3807 (1998) et al., 1998; KAKEYA, H., et al., Cancer Res. 58, 704-710 (1998); HARPER, J. W. Cancer Surveys 29, 91-107 (1997); HARRINGTON, E. A., et al., Proc. Natl. Acad. Sci. USA 95, 11945-11950 (1998); GARRETT, M. D. et al., Current Opin. Genetics Develop. 9, 104-111 (1999); MGBONYEBI, O. P., et al., Cancer Res. 59, 1903-1910 (1999)). All of these molecules bind at the ATP-binding site of the enzyme and are competitive with ATP.
Olomoucine is an inhibitor of Cdc2, CDK2, CDK5 and MAP kinase in micromolar concentrations and has much weaker effects toward CDK4 and CDK6 (GARRETT, M. D. Current Opin. Genetics Develop. 9, 104-111 (1999)). Olomoucine has been reported to arrest several cell lines in G1 and G2 phases of the cell cycle and block known CDK-dependent cellular activities.
Flavopiridol, a novel synthetic flavone, potently inhibits several cyclin-dependent kinases including CDK1, CDK2, CDK4 and CDK7 (SEDLACEK, H. H., et al., Int. J. Cancer 65, 1143-1168 (1996); CZECH, J., et al., Int. J. Oncol. 6, 31-36 (1995); BIBLE, K. C. et al., Cancer Res. 56, 4856-4861 (1996); SCHRUMP., D. S., et al., Clin. Cancer Res. 4, 2885-2890 (1998); BRUSSELBACH, S., et al., Int. J. Cancer, 77, 146-152 (1998); JAGER, W., et al., Life Sciences 62, 1861-1873 (1998); SENDEROWICZ, A. M., et al., J. Clin. Oncol. 16, 2986-2999 (1998)). Exposure to flavopiridol can cause cells to arrest in both the G1 and G2 phases of the cell cycle, at concentrations similar to those required for cell growth inhibition (BIBLE, K. C. et al., Cancer Res. 56, 4856-4861 (1996); SCHRUMP, D. S., et al., Clin. Cancer Res. 4, 2885-2890 (1998)). Flavopiridol inhibits the CDK""s in a manner competitive with ATP and noncompetitive with the substrate. Flavopiridol also inhibits other protein kinases such as protein kinase C, protein kinase A, and EGFR but at concentrations of 10 xcexcM/L or greater. Flavopiridol is an active antitumor agent in several human tumor xenograft models including Colo-205 colon carcinoma, and DU-145 and LNCaP prostate carcinomas (SEDLACEK, H. H., et al., Int. J. Cancer 65, 1143-1168 (1996); CZECH, J., et al., Int. J. Oncol. 6, 31-36 (1995)). Flavopiridol has shown completed Phase I clinical trial administered as a 72-hour continuous intravenous infusion every 2 weeks (SENDEROWICZ, A. M., et al., J. Clin. Oncol. 16, 2986-2999 (1998), and phase II trials are underway.
Much has already been published on the antineoplastic properties of certain compounds such as bisindolylmaleimides, indolocarbazoles, and derivations thereof. Staurosporine and UCN-01 are members of this broad molecular class (COLEMAN, K. G., et al., Ann. Reps. Med. Chem. 32, 171-179 (1997)). For example, U.S. Pat. No. 5,856,517 discloses substituted pyrroles, which are useful as antiproliferative agents in the treatment of cancer. U.S. Pat. No. 5,292,747 discloses substituted pyrroles useful in the prevention or control of oncological disorders. U.S. Pat. No. 5,721,245 discloses indolylpyrrolones useful in controlling oncological disorders. U.S. Pat. No. 5,438,050 (Godecke) discloses indolocarbazole derivatives useful in the prevention and treatment of cancer. U.S. Pat. No. 5,705,511 and U.S. Pat. No. 5,591,855 discloses fused pyrrolocarbazoles for the inhibition of growth associated with hyperproliferative states.
In addition to the kinases, which control the cell division cycle, there are over several hundred other kinases found in the human body. These kinases perform such diverse functions as growth factor and cytokine signal transduction, inflammatory mediators, biochemical routes controlling activity of nuclear transcription factors and apoptotic pathways. In treating proliferative diseases, it is particularly desirable to use a kinase inhibitor with a relatively narrow activity. Anti-cancer agents are generally given at high doses in order to kill as many cancerous cells as possible. With such high dosing, side effects due to broad kinase inhibition can become a serious problem. Accordingly, to treat proliferative diseases, it is desirable to use kinase inhibitors that are relatively selective for kinases controlling cell division.
The present invention provides compounds of Formula I 
where:
A and B are independently O or S;
X and Y are both hydrogen or, taken together, form a bond;
R1 is hydrogen or C1-C4 alkyl;
R5 and R5xe2x80x2 are optionally up to two substituents independently selected from the group consisting of halo, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkenyl, substituted C1-C6 alkenyl, C1-C6 alkoxy, aryloxy, benzyloxy, C1-C6 alkylthio and arylthio;
R6 and R6xe2x80x2 are optionally up to three substituents independently selected from C1-C4 alkyl;
R7 and R7xe2x80x2 are optionally substituents independently selected from (C1-C6 alkoxy)carbonyl or xe2x80x94(CH2)mxe2x80x94Z;
Z is halo, hydroxy, (C1-C6 alkyl)3SiOxe2x80x94, (diphenyl)(C1-C6 alkyl)SiO, carboxy, (C1-C4 alkoxy)carbonyl, or NR8R9;
R8 is hydrogen, C1-C6 alkyl, or substituted C1-C6 alkyl, C1-C6 alkenyl, substituted C1-C6 alkenyl,;
R9 is hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkenyl, substituted C1-C6 alkenyl, C1-C6 alkanoyl, substituted C1-C6 alkanoyl, tert-butoxycarbonyl, benzyloxycarbonyl, an amino acid residue, a protected amino acid residue, xcex2-(pyridinyl)alaninyl, aryl, heteroaryl, arylcarbonyl, or heteroarylcarbonyl; or
R8 and R9 taken together with the nitrogen to which they are attached form a saturated heterocycle optionally substituted with one or two hydroxy, amino, or C1-C6 alkyl groups;
Q1 and Q6 are independently O, S(O)n or xe2x80x94(CH2)1-3xe2x80x94;
Q2 and Q5 are independently selected from a carbon-carbon single bond, a carbon-carbon double bond, xe2x80x94NR10xe2x80x94, or xe2x80x94NR10xe2x80x94CHR11xe2x80x94;
Q3 and Q4 are independently selected from xe2x80x94(CH2)1-3xe2x80x94;
R10 is independently at each occurance hydrogen, (C1-C6 alkyl)sulfonyl, arylsulfonyl, hetroarylsulfonyl, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkenyl, substituted C1-C6 alkenyl, (C1-C5 alkyl)carbonyl, substituted (C1-C5 alkyl)carbonyl, an amino acid residue, a protected amino acid residue, xcex2-(pyridinyl)alaninyl, aryl, heteroaryl, arylcarbonyl, or heteroarylcarbonyl;
R11 is independently at each occurance hydrogen, C1-C6 alkyl, or substituted C1-C6 alkyl, C1-C6 alkenyl, substituted C1-C6 alkenyl; or R10 and R11 taken together with the atoms to which they are attached form a 5- or 6-membered saturated heterocycle;
m is independently at each occurance 0, 1, 2, 3, 4, or 5;
n is independently at each occurance 0, 1, or 2; or a pharmaceutically acceptable salt thereof.
The invention also provides pharmaceutical formulations comprising a compound of Formula I in combination with at least one pharmaceutically acceptable excipient.
Furthermore, the invention provides a method for the inhibition of CDK4 in a mammal comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I.
The invention also provides a method for the treatment of cell proliferative disorders in mammals comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I.
The invention also provides the use of a compound of Formula I for the preparation of a medicament useful for the inhibition of CDK4.
The invention further provides the use of a compound of Formula I for the preparation of a medicament useful for the treatment of a cell proliferative disorder.
The following definitions are to set forth the meaning and scope of the various terms used herein. The general terms used herein have their usual meanings.
As used herein, the term xe2x80x9chyperproliferative statexe2x80x9d refers to those cells whose unregulated and/or abnormal growth can lead to the development of an unwanted condition, for example, a cancerous condition or a psoriatic condition.
As used herein, the term xe2x80x9cpsoriatic conditionxe2x80x9d refers to disorders involving keratinocyte hyperproliferation, inflammatory cell infiltration, and cytokine alteration.
As used herein, the term xe2x80x9cneoplasmxe2x80x9d refers to an abnormal new growth of tissue that grows by cellular proliferation more rapidly than normal, continues to grow after the stimuli that initiated the new growth cease, shows partial or complete lack of structural organization and functional coordination with the normal tissue, and usually forms a distinct mass of tissue which may be either benign or malignant.
As used herein, the term xe2x80x9cproliferative diseasesxe2x80x9d refers to diseases in which some tissue in a patient proliferates at a greater than normal rate. Proliferative diseases may be cancerous or non-cancerous. Non-cancerous proliferative diseases include epidermic and dermoid cysts, lipomas, adenomas, capillary and cutaneous hemangiomas, lymphangiomas, nevi lesions, teratomas, nephromas, myofibromatosis, osteoplastic tumors, other dysplastic masses and the like.
The types of proliferative diseases which may be treated using the compositions of the present invention are epidermic and dermoid cysts, lipomas, adenomas, capillary and cutaneous hemangiomas, lymphangiomas, nevi lesions, teratomas, nephromas, myofibromatosis, osteoplastic tumors, other dysplastic masses and the like.
The types of cancers which may be treated with the compositions of the present invention include, but are not limited to, Breast Carcinoma, Bladder Carcinoma, Brain Cancer, Colorectal Carcinoma, Esophageal Carcinoma, Gastric Carcinoma, Germ Cell Carcinoma e.g. Testicular Cancer, Gynecologic Carcinoma, Hepatocellular Carcinoma, Small Cell Lung Carcinoma, Non-small Cell Lung Carcinoma, Lymphomas, Hodgkin""s Lymphoma, Non-Hodgkin""s Lymphoma, Malignant Melanoma, Multiple Myeloma, Neurologic Carcinoma, Ovarian Carcinoma, Pancreatic Carcinoma, Prostate Carcinoma, Renal Cell Carcinoma, Ewings Sarcoma, Osteosarcoma, Soft Tissue Sarcoma, Pediatric Malignancies and the like.
The general chemical terms used herein have their usual meanings. For example, as used herein, the term xe2x80x9calkyl,xe2x80x9d alone or in combination, denotes a straight-chain or branched-chain C1-C6 alkyl group consisting of carbon and hydrogen atoms, examples of which are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and the like. The term xe2x80x9cC1-C6 alkylxe2x80x9d also refers to C3-C6 cycloalkyl, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term xe2x80x9calkenyl,xe2x80x9d alone or in combination, denotes a straight-chain or branched-chain C2-C6 alkenyl group consisting of carbon and hydrogen atoms and containing a carbon-carbon double bond, examples of which are ethylene, propylene, methylethylene, butylene, and the like.
The term xe2x80x9calkoxy,xe2x80x9d alone or in combination, denotes an alkyl group as defined earlier which is attached via an oxygen atom, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, and the like.
As used herein, the term xe2x80x9csubstituted C1-C6 alkylxe2x80x9d represents a straight or branched alkyl chain substituted with a carboxyl, (C1-C6 alkoxy)carbonyl, C1-C6 alkoxy, aryloxy, amino, (C1-C6 alkyl)amino, tetrahydrofuryl or up to one hydroxy moiety for each carbon atom an the alkyl chain.
As used herein, the term xe2x80x9carylxe2x80x9d represents a phenyl or naphthyl moiety optionally substituted with from one to three substituents selected from halo, C1-C6 alkyl, hydroxy, amino or C1-C6 alkoxy.
As used herein, the term xe2x80x9cheteroarylxe2x80x9d means a stable one- or two-ring aromatic moiety that comprised of carbon atoms and 1-4 heteroatoms selected from O, S, and N. Examples of heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, triazinyl, phthalimido, indolyl, purinyl, benzothiazolyl, and the like. The heteroaryl moiety may be optionally substituted with one or two groups independently selected from amino, hydroxy, C1-7 alkoxy, aryloxy, C1-7 alkyl, aminoalkyl, haloalkyl and halogen.
As used herein, the term xe2x80x9csaturated heterocyclexe2x80x9d is taken to be a 4-9 membered ring containing nitrogen and optionally one other atom selected from oxygen, nitrogen, or sulfur.
As used herein, the term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d or xe2x80x9chalidexe2x80x9d represents fluorine, chlorine, bromine, or iodine. A haloalkyl is one such alkyl substituted with one or more halo atoms, preferably one to three halo atoms. However, all the hydrogen atoms in alkyl group may be replaced by halogens. As more halogens are added to an alkyl group, fluorine is preferred over the other halogens. An example of a haloalkyl is trifluoromethyl.
As used herein, an xe2x80x9camino acid residuexe2x80x9d is taken to mean the product of an amino acid coupled to the compound of Formula I through the carboxylic acid moiety, forming an amide or ester bond, or through the xcex1- or xcex2-amino moiety, forming an amide or amine bond.
As used herein, a xe2x80x9cprotected amino acid residuexe2x80x9d is taken to mean an amino acid residue where the amine or carboxylic acid moieties not participating in the bond to the compound nucleus are protected by suitable protecting groups. Such groups include tert-butyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, and the like.
As used herein, the term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d includes acid and base addition salts. Such pharmaceutically acceptable salts include inorganic acid addition salts such as hydrochloride, sulfate, and phosphate, and organic acid addition salts such as acetate, maleate, fumarate, tartrate, and citrate. Examples of pharmaceutically acceptable basic salts include metal salts such as the alkali metal salts such as the sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt. Examples of pharmaceutically acceptable ammonium salts are ammonium salt and tetramethylammonium salt. Examples of pharmaceutically acceptable amine addition salts are salts with morpholine and piperidine. Examples of pharmaceutically acceptable amino acid addition salts include salts with lysine, glycine, and phenylalanine. Preferred salts include those with hydrochloric acid, trifluoroacetic acid, and methanesulfonic acid.
As used herein the term xe2x80x9camino acidxe2x80x9d includes both naturally occurring and synthetic amino acids and includes both the D and L forms of the acids as well as the racemic form. More specifically, amino acids contain up to ten carbon atoms. They may contain an additional carboxyl group, and heteroatoms such as nitrogen and sulfur. Preferably the amino acids are xcex1- and xcex2-amino acids. The term a-amino acid refers to amino acids in which the amino group is attached to the carbon directly attached to the carboxyl group, which is the a-carbon. The term xcex2-amino acid refers to amino acids in which the amino group is attached to a carbon two removed from the carboxyl group, which is the xcex2-carbon. Some common xcex1-amino acid residues are shown in Table I wherein the residues are given the name of the amino acids from which they are derived.
Suitable xcex2-amino acid residues can be the xcex2-amino derivative of any suitable xcex1-amino acid residue wherein the amino group is attached to the residue through the xcex2-carbon rather than the xcex1-carbon relative to the carboxyl group, for example, 3-aminopropionoic acid, 3-amino-3-phenylpropionoic acid, 3-aminobutyric acid and the like: 
Although all of the compounds of Formula I are useful CDK4 inhibitors, certain compounds are preferred. The following paragraphs define preferred classes.
aa) A and B are both oxygen;
ab) X and Y, taken together, form a bond;
ac) R1 is hydrogen;
ad) R5 is halogen;
ae) R6 is geminal dimethyl;
af) R7 is xe2x80x94(CH2)mxe2x80x94Z;
ag) R7 is hydroxymethyl;
ah) R5xe2x80x2 is halogen;
ai) R6xe2x80x2 is geminal dimethyl;
aj) R7xe2x80x2 is xe2x80x94(CH2)mxe2x80x94Z;
ak) R7xe2x80x2 is hydroxymethyl;
al) m is 0;
am) m is 1, 2, or 3;
an) m is 1;
ao) Z is (C1-C4 alkoxy)carbonyl;
ap) Z is methoxycarbonyl;
aq) Z is hydroxy;
ar) Z is NR8R9;
as) R8 and R9 taken together with the nitrogen to which they are attached form an aziridinyl, pyrrolidinyl, 3-hydroxypyrrolidinyl, piperidinyl, piperazinyl, 4-(tert-butoxycarbonyl)piperazin-4-yl, or diazepinyl;
at) Q2 is a carbon-carbon single bond;
au) Q2 is xe2x80x94NR10xe2x80x94;
av) Q2 is xe2x80x94NR10xe2x80x94CHR11xe2x80x94;
aw) Q5 is a carbon-carbon single bond;
ax) Q5 is xe2x80x94NR10xe2x80x94;
ay) Q5 is xe2x80x94NR10xe2x80x94CHR11xe2x80x94;
az) Q1, Q2, and Q3, taken together with the atoms to which they are attached, form a 6-membered ring, a 7-membered ring, or an 8-membered ring;
ba) Q1, Q2, and Q3, taken together with the atoms to which they are attached, form an unsubstituted ring;
bb) Q1 is xe2x80x94(CH2)xe2x80x94;
bc) Q1 is xe2x80x94(CH2)2xe2x80x94;
bd) Q3 is xe2x80x94(CH2)xe2x80x94;
be) Q3 is xe2x80x94(CH2)2xe2x80x94;
bf) Q3 is xe2x80x94(CH2)3xe2x80x94;
bg) Q4, Q5, and Q6, taken together with the atoms to which they are attached, form a 6-membered ring, a 7-membered ring, or an 8-membered ring;
bh) Q4, Q5, and Q6, taken together with the atoms to which they are attached, form an unsubstituted ring;
bi) Q6 is xe2x80x94(CH2)xe2x80x94;
bj) Q6 is xe2x80x94(CH2)2xe2x80x94;
bk) Q4 is xe2x80x94(CH2)xe2x80x94;
bl) Q4 is xe2x80x94(CH2)2xe2x80x94;
bm) Q4 is xe2x80x94(CH2)3xe2x80x94;
bn) Q2 is a carbon-carbon single bond and Q5 is xe2x80x94NR10xe2x80x94 or xe2x80x94NR10xe2x80x94CHR11xe2x80x94;
bo) R10 is methanesulfonyl;
bq) R10 is heteroarylsulfonyl;
br) R10 is C1-C4 alkyl;
bs) R10 is hydrogen.
The preceding paragraphs may be combined to define additional preferred classes of compounds.
The compounds of Formula I are useful for the treatment of disorders of mammals, and the preferred mammal is a human.
The skilled artisan will appreciate that the introduction of certain substituents will create asymmetry in the compounds of Formula I. The present invention contemplates all enantiomers and mixtures of enantiomers, including racemates. It is preferred that the compounds of the invention containing chiral centers are single enantiomers.
Variables R5, R5, R6, R6, R7 and R7 may optionally be selected from specified groups. A preferred embodiment of the invention are those compounds where no substituent is selected from said groups.
The carbazoles, compounds of Formula I where X and Y taken together form a bond, are prepared by oxidation of the corresponding maleimide, compounds of Formula I where X and Y are each hydrogen. This oxidative step is illustrated in Scheme I, where the ring designated xe2x80x9cAxe2x80x9d corresponds to the annulated rings of Formula I. The skilled artisan will appreciate that the transformations illustrated in the following schemes are not limited to the unsubstituted compounds represented. Substituents have been eliminated in the following schemes for the sake of clarity, and are not intended to limit the teaching of the schemes in any way. 
This transformation may be prepared by a number of methods. For example, the maleimide of formula (ii) in an appropriate solvent, such as acetic acid, may be treated with a palladium salt such as palladium dichloride, palladium bis(trifluoroacetate), or preferably palladium diacetate. The reaction is conducted at a temperature of about 60xc2x0 C. to about reflux, and the mixture is stirred for 1-24 hours. The resulting carbazole of formula (i) is recovered by standard isolation techniques and may be purified by chromatography or recrystallization as necessary or desired.
Alternatively, a mixture of a maleimide of formula (Ii) in a suitable solvent, such as benzene, an acid, such as para-toluenesulfonic acid monohydrate, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is stirred at about reflux for 1-6 hours, after which the mixture is allowed to cool to about ambient temperature and stirred for an additional 1-24 hours. The resulting carbazole of formula (i) is isolated and purified by standard techniques.
Furthermore, a maleimide of formula (ii) and iodine in a suitable solvent, such as dioxane, may be reacted via irradiation by a medium-pressure mercury lamp. The reaction mixture is irradiated for about 10 minutes to about 24 hours. The resulting carbazole formula (i) may be isolated and purified by standard techniques.
The requisite maleimides of formula (ii) may be prepared from an appropriately substituted oxoacetic acid ester and an appropriately substituted acetamide as illustrated in Scheme II, where the ring designated xe2x80x9cAxe2x80x9d corresponds to the annulated rings of Formula I. 
The oxoacetic acid esters of formula (iii) are reacted with an acetamide of formula (iv), in a suitable solvent, such as tetrahydrofuran, in the presence of a suitable base, preferably potassium tert-butoxide. The condensation reaction is conducted at 0xc2x0 C. or room temperature, and the reactants are stirred for 1-24 hrs. The reaction mixture was treated with a suitable acid, such as hydrochloric acid, after which the mixture is stirred at about ambient temperature for 1-24 hours. The resulting maleimide (ii) may be isolated by standard techniques, and purified by crystallization or chromatography as necessary or desired.
The requisite annulated-indole acetamides (iv) may be prepared from the corresponding annulated-indole oxoacetic acid esters (iii) by reaction with ammonium hydroxide in a suitable solvent, such as tetrahydrofuran or diethyl ether. The reaction is conducted at about 0xc2x0 C. for 1-12 hours, after which the reaction mixture is allowed to warm to about ambient temperature. The resulting ketoamide may be isolated by standard techniques and purified by crystallization or chromatography as necessary or desired. This ketoamide is then reduced by reaction with a precious metal catalyst, such as palladium, and sodium hypophosphite in a suitable solvent, such as tetrahydrofuran, dioxane, or dimethylformamide. The reaction is conducted under nitrogen at about reflux conditions for 1-12 hours. The resulting acetamide is isolated by standard techniques and may be purified by crystallization or chromatography as necessary or desired.
The annulated-indole oxoacetic acid esters (iii) may be prepared by reacting an appropriately substituted annulated-indole with oxalyl chloride in an appropriate solvent, such as dichloromethane or diethyl ether. The addition is performed at a temperature of about 0xc2x0 C., and the mixture is stirred for 30-120 minutes. The mixture is then cooled to about xe2x88x9278xc2x0 C. and than a source of alkoxide, such as sodium methoxide, is added in an appropriate solvent, such as methanol. The resulting oxoacetic acid ester may be isolated by standard techniques and purified by crystallization or chromatography as necessary or desired.
The requisite annulated-indoles are prepared by a variety of methods depending upon the specific structure of the ring system. Synthetic methodologies leading to the various annulated-indoles are illustrated in the following schemes and discussed in the following paragraphs. The preparations and examples further illustrate these basic routes as well as modifications to these routes to prepare certain requisite substituted variants.
4,5-dihydropyrrolo[3,2,1-hi]indoles 
An N-aminoindoline (Wijngaarden, et al., J. Med. Chem., 36, 3693 (1993)) is treated with ethyl pyruvate in a suitable solvent, such as ethanol, at reflux. After about an hour, the imine from this reaction is dissolved in a suitable solvent, such as acetic acid, and is treated with an appropriate Lewis acid, such as boron trifluoride etherate, at reflux for about an hour. The resulting ethyl pyrroloindole-2-carboxylic acid is isolated by standard conditions. The ester is hydrolyzed to provide the corresponding carboxylic acid under standard conditions, and then is decarboxylated in the presence of copper(II) oxide in quinoline to provide compounds of formula (viii).
5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolines 
An appropriately substituted 1,2,3,4-tetrahydroquinoline is reacted with ethyl bromopyruvate in an appropriate solvent, such as dimethylformamide or tetrahydrofuran. The reaction mixture is stirred for 1-30 hours. The product from this reaction is isolated by standard techniques and is then reacted with an appropriate magnesium halide, typically magnesium chloride, and an appropriate alcohol in an appropriate solvent, such as tetrahydrofuran or dimethylformamide. The skilled artisan will appreciate that the addition must be performed slowly and carefully, after which the resulting reaction mixture is stirred for 1-12 hours at about reflux. The resulting carboxylic acid ester is isolated by standard techniques. This ester is then hydrolyzed and decarboxylated under standard conditions to provide compounds of formula (ix).
3,4-Dihydro-5-thia-2a-aza-acenaphthalene and 3,4-Dihydro-5-oxo-2a-aza-acenaphthalene 
Compounds of formula (x) are prepared beginning with 3,4-dihydro-2H-benzo[1,4]thiazine or 3,4-dihydro-2H-benzo[1,4]oxazine by the same techniques described for the compounds of formula (ix). The corresponding sulfoxide and sulfones may be prepared at any convenient point in the synthesis by oxidation with an appropriate reagent, such as meta-chloroperbenzoic acid.
4,5,6,7-tetrahydroazepino[3,2,1-hi]indole 
An appropriately substituted 1-tetralone is reacted with hydroxylamine hydrochloride under standard conditions to provide the corresponding oxime. This oxime is heated in a strong acid, such as polyphosphoric acid, for about 10 minutes. The reaction mixture was treated with ice and water to precipitate the corresponding 1,3,4,5-tetrahydro-benz[b]azepin-2-one. This lactam is reduced under standard conditions to provide the corresponding 2,3,4,5-tetrahydro-1H-benzo[b]azepine. Reaction of this amine with ethyl bromopyruvate, followed by treatment with magnesium chloride, ester hydrolysis, and decarboxylation as described above for compounds of formula (ix), provides the compounds of formula (xi).
5,6-dihydro-6H-[1,4]diazepino[6,7,1-hi]indoles 
An appropriately substituted indole-7-carboxaldehyde in an appropriate solvent, such as 1,2-dichloroethane, is reacted with an appropriately substituted amino acid methyl ester and acetic acid. This reaction is conducted under nitrogen at about ambient temperature in the presence of a mild reducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride. The reaction mixture is stirred for about 24 hours, and the resulting amino ester is isolated by standard techniques. The ester moiety is reduced to the corresponding alcohol by treatment with a suitable reducing agent, typically lithium aluminum hydride, in an appropriate solvent, typically tetrahydrofuran or diethyl ether. The secondary amine moiety is now reacted with an appropriate reagent to introduce a suitable amino protecting group xe2x80x9cPgxe2x80x9d, such as a formyl group, acetyl group, or preferably a tert-butoxycarbonyl moeity. Techniques for the introduction of these groups are well known to the skilled artisan. A solution of this compound in an appropriate solvent, such as dichloromethane or diethyl ether, is reacted with an appropriate reagent to activate the hydroxy moiety, providing a leaving group (xe2x80x9cLgxe2x80x9d). The skilled artisan would appreciate that appropriate leaving groups include halides, oxonium ions, alkyl perchlorates, ammonioalkanesulfonate esters, alkyl fluorosulfonates, nonaflates, tresylates, triflates, and sulfonic esters, preferably the mesylate or tosylate. Techniques for the introduction of these groups are well known to the skilled artisan. (See for example: March, xe2x80x9cAdvanced Organic Chemistry,xe2x80x9d John Wiley and Sons, New York, N.Y., 1992, pg. 352-362). The activated compound is then dissolved in an appropriate solvent, such as tetrahydrofuran or diethyl ether, and is reacted with a strong base, such as potassium hydride or sodium hydride. The reaction is conducted under nitrogen at about 0xc2x0 C. and stirred for 30-120 minutes. The compound of formula (xii) is isolated and purified by standard techniques. The skilled artisan will appreciate that the nitrogen-protecting groups may be removed at any convenient point in the synthesis of the compounds of the present invention. Methods of removing an amino-protecting group are well known in the art (for example, see: T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d John Wiley and Sons, New York, N.Y., 1991, Chapter 7).
5,6-dihydro-6H-[1,4]homodiazepino-[6,7,1-hi]indoles 
An appropriately substituted indole-7-carboxaldehyde in an appropriate solvent, such as tetrahydrofuran or toluene, is reacted with a suitable methylenating reagent at about ambient temperature. Suitable methylenating reagents include Tebbe reagent (xcexc-chloro-xcexc-methylene[bis(cyclopentadienyl)titanium]dimethylaluminum) and appropriate Wittig reagents, such as methyltriphenylphosphonium bromide, in the presence as a suitable base, such as potassium tert-butoxide. The reaction mixture is stirred for 1-6 hours, after which the resultant vinylindole is isolated under standard techniques. This compound is then hydroborated and oxidized under standard conditions to provide the corresponding hydroxyethylindole. This alcohol is then activated as previously described, and reacted with ethanolamine or an appropriate amino acid ester. When aminoethanol is employed, the resulting alcohol is activated and the compound cyclized as previously described. When an amino acid ester is employed, the resulting ester is first reduced, and then activated and the compound cyclized as previously described to provide compounds of formula (xiii). The skilled artisan will appreciate that the nitrogen-protecting groups may be removed at any convenient point in the synthesis of the compounds of the present invention.
Pyrrolo[3,2,1-kl]benzo[b]azacyclooctane 
An appropriately substituted 7-vinylindole is alkylated with an appropriate bromoalkene under standard conditions and the resulting diene is reacted with bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride (Grubb""s catalyst) at room temperature in a suitable solvent, such as dichloromethane. After about 24 hours the cyclized alkene is isolated by standard techniques. The double bond may then be reduced under standard hydrogenation conditions to provide the compounds of formula (xiv).
[1,5]diazaperhydroonino[8,9,1-hi]indoles 
An appropriately substituted indole-7-carboxaldehyde was reductively aminated with allylamine in the presence of a suitable acid, such as acetic acid, and an appropriate reducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride in an appropropriate solvent, such as 1,2-dichloroethane. The mixture is stirred at room temperature for about 24 hours and the resulting amine is isolated and purified by standard techniques. The amine is then protected as previously described and the indole nitrogen alkylated with allyl bromide under standard conditions. The diene is then cyclized as previously described to provide the cyclic alkene. The double bond may then be reduced under standard hydrogenation conditions to provide the compounds of formula (xv).
The skilled artisan will appreciate that compounds of the invention where variables A and B are independently S may be prepared by treating either the final compound or an appropriate carbonyl starting material with [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (Lawesson""s Reagent) or phosphorus pentasulfide.
Many of the compounds of the present invention are not only inhibitors of CDK4, but are also useful intermediates for the preparation of additional compounds of the present invention. For example, secondary amines may be acylated, alkylated or coupled with simple carboxylic acids or amino acids under standard conditions. Furthermore, ester moieties may be reduced to the corresponding alcohols. These alcohols may then be activated and displaced by a number of nucleophiles to provide other compounds of the invention. The skilled artisan will also appreciate that not all of the substituents in the compounds of Formula I will tolerate certain reaction conditions employed to synthesize the compounds. These moieties may be introduced at a convenient point in the synthesis, or may be protected and then deprotected as necessary or desired. Furthermore, the skilled artisan will appreciate that in many circumstances, the order in which moieties are introduced is not critical. The following preparations and examples will further illustrate the preparation of compounds of the present invention.
3-(3,4-Dihydro-2H-quinolin-1-yl)-2-oxopropionic acid ethyl ester
To a solution of 1,2,3,4-tetrahydroquinoline (75.5 mL, 0.59 mol) in tetrahydrofuran (300 mL) was added bromoethyl pyruvate (40 mL, 0.29 mol) dropwise over 30 minutes. Following 24 hours of stirring, the reaction mixture was filtered, the filter cake rinsed well with tetrahydrofuran (100 mL) and the filtrate concentrated under reduced pressure to dryness to give 79.7 g of the desired compound as a red oil.
5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid ethyl ester
Magnesium chloride (27.7 g, 0.29 mol) was added to 2-methoxyethanol (400 mL) and the mixture heated to reflux. A solution of 3-(3,4-Dihydro-2H-quinolin-1-yl)-2-oxopropionic acid ethyl ester (0.29 mol) in 2-methoxyethanol (100 mL) and tetrahydrofuran (40 mL) was slowly added to the MgCl2 mixture over 1 hour. Upon completion of addition, the mixture was stirred for 5 hours at reflux, and then concentrated in vacuo. The concentrated crude mixture was treated with 2N hydrochloric acid (500 mL) and extracted with dichloromethane (3xc3x97400 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography, eluting with 20% ethyl acetate/hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 31.6 g (48%) of the desired compound as an orange solid.
MS (IS, m/z) C14H15NO2 (M++1)=230.
5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid
To a solution of 5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid ethyl ester (31 g, 0.14 mol) in ethanol (200 mL) and water (70 mL) was added 5 N aqueous sodium hydroxide(60 mL, 0.3 mol) and the resulting mixture stirred at reflux for 3 hours. The reaction mixture was cooled to 20-24xc2x0 C., diluted with water (2 L) and washed with dichloromethane(2xc3x97200 mL) and diethyl ether (1xc3x97200 mL). The aqueous layer was filtered through Celite and the filtrate was acidified with conc. HCl (25 mL) to precipitate the product. The solid was filtered, washed with water (200 mL), and dried in vacuo to give 23.2 g (85%) of the desired compound as a light yellow solid.
MS (IS, m/z) C12H11NO2 (M++1)=202.
Decarboxylation
To a solution of 5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid (3.7 g, 18.4 mmol) in 20 mL of quinoline was added copper chromite (1.5 g, 4.8 mmol). The resulting mixture was stirred at 185xc2x0 C. for 4 hours and then cooled to 20-24xc2x0 C., diluted with dichloromethane (100 mL) and filtered through Celite. The filtrate was then washed sequentially with 2 N hydrochloric acid (2xc3x9750 mL) and 2 N aqueous sodium hydroxide (25 mL). The remaining organic phase was concentrated in vacuo. The residue was subjected to silica gel chromatography, eluting with 5% EtOAc/Hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 1.67 g (58%) of the desired compound as a light tan solid.
1H NMR (400 MHz, DMSO-d6) xcex47.31-7.29 (d, 1H, J=7.8 Hz), 7.28-7.27 (d, 1H, J=2.93 Hz), 6.9-6.86 (t, 1H, J=7.6 Hz), 6.82-6.8 (dd, 1H, J=6.8, 1.0 Hz), 6.33-6.32 (d, 1H, J=2.93 Hz), 4.15-4.12 (t, 2H, J=5.6 Hz), 2.92-2.89 (t, 2H, J=6.1 Hz), 2.15-2.08 (m, 2H).
To a solution of 5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinoline (1.67 g, 10.6 mmol) in 150 mL of anhydrous diethyl ether at 0xc2x0 C. was added dropwise oxalyl chloride (1.05 mL, 12.08 mmol) and the resulting solution was stirred at 0xc2x0 C. for 40 minutes. The mixture was then cooled to xe2x88x9278xc2x0 C. and sodium methoxide (42 mL, 21 mmol, 0.5 M in methanol) was added slowly. Upon completion of the addition, the dry ice bath was removed and the reaction was warmed to 20-24xc2x0 C. over 2 hours. The mixture was diluted with ethyl acetate (200 mL), washed with water (100 mL) and the layers were separated. The organic layer was washed with saturated aqueous sodium chloride (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL), filtered through a 2 inch plug of coarse silica gel and concentrated in vacuo to give 2.16 g (84%) of the desired compound as a yellow solid.
MS (EI, m/z) C14H13NO3 (M+xe2x88x9259)=184.
Beginning with 8-fluoro-6,6-dimethyl-4,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline, the title compound was prepared essentially as described in Preparation II.
MS(ES): m/e=290 (M+1)
EA: Calculated for: C16H16FNO3: Theory: C, 66.43; H, 5.58; N, 4.84. Found: C, 66.29; H, 5.50; N, 4.90.
S-3-(tert-Butoxy)-2-(N-[(1H-indol-7-yl)methyl]amino)-propionic acid methyl ester
To a solution of indole-7-carboxaldehyde (0.500 g, 3.44 mmol) in 1,2-dichloroethane (30 mL) under nitrogen was added Sxe2x80x94(O-tert-butyl)serine methyl ester hydrochloride (1.09 g, 5.16 mmol), acetic acid (0.206 g, 0.197 mL, 3.44 mmol), and sodium triacetoxyborohydride (1.46 g, 6.88 mMol). The resulting mixture was stirred at 20-24xc2x0 C. for 24 hours. The reaction mixture was then quenched by the addition of aqueous saturated sodium bicarbonate. The organic phase was extracted with dichloromethane and washed with saturated aqueous sodium chloride. The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with ethyl acetate:hexane (3:7). Fractions containing product were combined and concentrated under reduced pressure to give 0.96 g (92%) of the desired product as an oil.
MS (ES, m/z) (M+1)=305.0
S-3-(tert-Butoxy)-2-(N-[(1H-indol-7-yl)methyl]amino)propan-1-ol
To a solution of S-3-(tert-Butoxy)-2-(N-[(1H-indol-7-yl)methyl]amino)propionic acid methyl ester (0.960 g, 3.15 mmol) in tetrahydrofuran (20 ml) at xe2x88x9278xc2x0 C. was added lithium aluminum hydride (1 M in toluene, 6.31 mL) dropwise. The resulting reaction solution was warmed to 0xc2x0 C. and stirred for 1 hour then warmed to 20-24xc2x0 C. and stirred for 1 hour. It was cooled to 0xc2x0 C., and was then quenched by the sequential addition of methanol followed by water. The suspension was filtered, washed with methanol and the filtrate concentrated under reduced pressure. The residue was dissolved in ethyl acetate, dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with methanol:ethylacetate (1:9). Fractions containing product were combined and concentrated under reduced pressure to provide 0.51 g (59%) of the desired compound.
MS (ES, m/z) (Mxe2x88x921)=275.1, (M+1)=277.1.
S-3-(tert-Butoxy)-2-(N-[(1H-indol-7-yl)methyl]-N-[tert-butoxycarbonyl]amino)propan-1-ol
A solution of S-3-(tert-Butoxy)-2-(N-[(1H-indol-7-yl)methyl]amino)propan-1-ol (0.510 g, 1.85 mmol) and di(tert-butyl) dicarbonate (0.480 g, 2.21 mmol) in tetrahydrofuran (20 ml) was refluxed under nitrogen for 1.5 hours. The reaction mixture was cooled to room temperature and was then concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with ethyl acetate:hexane (1:1). Fractions containing product were combined to provide 0.58 g (84%) of the desired product as an oil.
MS (ES, m/z) (M+1)=377.1, (Mxe2x88x921)=375.1.
S-3-(tert-Butoxy)-2-(N-[(1H-indol-7-yl)methyl]-N-[tert-butoxycarbonyl]amino)-1-(methanesulfonyloxy)propane
To a solution S-3-(tert-Butoxy)-2-(N-[(1H-indol-7-yl)methyl]-N-[tert-butoxycarbonyl]amino)propan-1-ol (0.522 g, 1.39 mmol) in dichloromethane (15 ml) at 0xc2x0 C. under nitrogen was added triethylamine (0.94 mL, 0.680 g, 6.70 mmol) followed by the dropwise addition of a solution of methanesulfonyl chloride (0.159 g, 1.39 mmol) in dichloromethane (5 ml). The resulting solution was stirred at 0xc2x0 C. for 1 hour. Ice-cooled water was added and the resulting mixture was extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was used without further purification.
MS (ES, m/z) (Mxe2x88x921)=453.1
Ring Closure
To a solution of S-3-(tert-Butoxy)-2-(N-[(1H-indol-7-yl)methyl]-N-[tert-butoxycarbonyl]amino)-1-(methanesulfonyloxy)propane in dimethylformamide at 0xc2x0 C. under nitrogen was added sodium hydride (0.083 g, 2.09 mmol, 60% suspension in oil). The mixture was stirred for 1 hour and then it was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic phase was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with ethyl acetate:hexane (1:1). Fractions containing product were combined and concentrated under reduced pressure to provide 0.34 g (68%) of the title compound as a white solid.
MS (ES, m/z) (M+1)=359.1
To a solution of S-6-(tert-butoxycarbonyl)-5-(tert-butoxy)methyl-5,6-dihydro-6H-[1,4]diazepino[6,7,1-hi]indole (0.330 g, 0.920 mmol) in dichloromethane (10 ml) at 0xc2x0 C. under nitrogen was added oxalyl chloride (0.46 ml, 0.920 mmol, 1M in dichloromethane) dropwise. The mixture was stirred at 0xc2x0 C. for 1 hour and then cooled to xe2x88x9278xc2x0 C. Sodium methoxide (0.40 ml, 1.84 mmol, 4.63 M in methanol) was added and the resulting reaction mixture was warmed to room temperature. The mixture was then washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with ethyl acetate:hexane (1:1). Fractions containing product were combined and concentrated under reduced pressure to provide 0.35 g (85%) of the title compound as a white solid.
MS (ES, m/z) (M+1) 445.1.
6-(tert-butoxycarbonyl)-5-methyl-5,6-dihydro-6H-[1,4]diazepino[6,7,1-hi]indole
Beginning with indole-7-carboxaldehyde and DL-alanine methylester hydrochloride (0.72 g, 5.16 mmol), the title compound was prepared essentially as described in Preparation IV.
MS (ES, m/z) (M+1)=287.0.
Beginning with 6-(tert-butoxycarbonyl)-5-methyl-5,6-dihydro-6H-[1,4]diazepino[6,7,1-hi]indole, the title compound was prepared essentially as described in Preparation V.
MS (ES, m/z) (M+1)=373.0
Beginning with indole-7-carboxyaldehyde and Sxe2x80x94(O-tert-butyl)tyrosine methyl ester hydrochloride, the title compound was prepared essentially as described in Preparation IV.
MS (ES, m/z) 435.1 (M+1)
Beginning with S-6-(tert-butoxycarbonyl)-5-(4-tert-butoxyphenyl)methyl-5,6-dihydro-6H-[1,4]diazepino [6,7,1-hi]indole, the title compound was prepared essentially as described in Preparation V.
MS (ES, m/z) 521.1 (M+1).
3,4-Dihydro-2H-naphthalen-1-one oxime
To a solution of xcex1-tetralone (100.0 g, 0.68 mol) in 300 mL of methanol was added hydroxylamine hydrochloride (71.0 g, 1.03 mol) and the resulting solution was stirred at reflux for 2 hours. The mixture was allowed to cool to 20-24xc2x0 C. and was concentrated under reduced pressure. The resulting mixture was diluted with 1 L of water and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from isopropanol to provide 70.0 g (63%) of the desired compound as an off-white solid.
MS (FIA, m/z) C10H11NO (M++1)=162.4.
1,3,4,5-Tetrahydrobenzo[b]azepin-2-one
A 1 L 3-neck round bottom flask equipped with a mechanical stirrer was charged with neat polyphosphoric acid (100 g) and the acid heated to 125xc2x0 C. while being stirred under nitrogen. 3,4-Dihydro-2H-naphthalen-1-one oxime (15.0 g, 93 mmol) was added carefully to control exotherm, keeping the temperature below 175xc2x0 C. Following 10 minutes of heating the mixture was cooled to 20-24xc2x0 C. and the reaction quenched with ice and water to generate a precipitate. The aqueous suspension was filtered and the precipitate washed with water until the filtrate became neutral. The filtered solid was dried under vacuum to provide 12.8 g (85%) of the desired compound as an off-white solid.
MS (ES, m/z) C10H11NO (M++1)=161.9
2,3,4,5-Tetrahydro-1H-benzo[b]azepine
To a solution of 1,3,4,5-tetrahydrobenzo[b]azepin-2-one (12.9 g, 80.0 mmol) in 720 mL of tetrahydrofuran was added 80 mL of lithium aluminum hydride (1 M solution in tetrahydrofuran). The reaction mixture was stirred at reflux for 3 hours and cooled to 0xc2x0 C. The reaction was quenched by the sequential addition of 3 mL of water, 3 mL of 15% sodium hydroxide, and 9 mL of water. The mixture was filtered through Celite and the filter cake rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure to provide 10.0 g (85%) of the desired compound as an orange solid.
MS (FIA, m/z) C10H13N (M++1)=148.2.
2-Oxo-3-(2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-propionic acid ethyl ester
To a 0xc2x0 C. suspension of 60% sodium hydride (3.0 g, 0.12 mol) in 300 mL of dimethylformamide was added 2,3,4,5-tetrahydro-1H-benzo[b]azepine in small portions. Upon complete addition of the amine, the ice bath was removed and the reaction stirred at 20-24xc2x0 C. for 40 minutes. Ethyl bromopyruvate (22.6 mL, 0.16 mol) was then added and the resulting mixture stirred at 20-24xc2x0 C. for 6 hours. An additional 5 mL of ethyl bromopyruvate was added and the mixture stirred for 1 hour. The reaction was quenched by the addition of 50 mL of water followed by dilution with 1.5 L of dichloromethane. The layers were separated and the organic layer was washed with water (2xc3x97500 mL) and saturated aqueous sodium chloride (500 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure at 60xc2x0 C. The residual brown oil was dissolved in ethyl acetate (500 mL) and was washed 3 times with water (100 mL) and once with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 5-10% EtOAc/hexanes to provide 7.0 g (40%) of the desired compound as an off white solid.
MS (FID, m/z) C15H19NO3 (M+)=261.13.
4,5,6,7-Tetrahydroazepino[3,2,1-hi]indole-1-carboxylic acid ethyl ester
Magnesium chloride (2.55 g, 26.8 mmol) was added to 30 mL of 2-methoxyethanol and the mixture heated to reflux. A solution of 2-oxo-3-(2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-propionic acid ethyl ester (7.0 g, 26.8 mmol) in 2-methoxyethanol (20 mL) was slowly added to the MgCl2 mixture over 1 hour. The resulting mixture was stirred for 6 hours at reflux, cooled to 20-24xc2x0 C. and concentrated under reduced pressure. The residue was diluted with 400 mL of dichloromethane and washed with 2 N hydrochloric acid (100 mL), followed by saturated aqueous sodium bicarbonate (100 mL) and finally saturated aqueous sodium chloride (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. This residue was subjected to silica gel chromatography, eluting with 20% EtOAc/Hexane. Fractions containing product were combined and concentrated under reduced pressure to provide 3.1 g (48%) of the desired compound as a yellow oil.
MS (FIA, m/z) C15H17NO2 (M++1)=244.4.
4,5,6,7-Tetrahydroazepino[3,2,1-hi]indole-1-carboxylic acid
To a solution of 4,5,6,7-tetrahydroazepino[3,2,1-hi]indole-1-carboxylic acid ethyl ester (2.0 g, 8.22 mmol) in ethanol (13 mL) and water (9 mL) was added powdered sodium hydroxide (0.71 g, 17.8 mmol) and the resulting mixture stirred at reflux for 4 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and washed with dichloromethane (2xc3x9750 mL). The layers were separated and the aqueous layer was filtered through Celite and the filtrate was acidified with concentrated hydrochloric acid. The suspension was filtered and the recovered solid washed with water and dried under reduced pressure to provide 1.59 g (90%) of the desired compound as a white solid.
MS (FIA, m/z) C13H13NO2 (M++1)=216.3
Decarboxylation
To a solution of 4,5,6,7-tetrahydroazepino[3,2,1-hi]indole-1-carboxylic acid (1.4 g, 6.5 mmol) in 7.5 mL of quinoline was added copper chromite (0.55 g, 1.77 mmol). The resulting mixture was stirred at 185xc2x0 C. for 4 hours and then cooled to room temperature, diluted with dichloromethane and filtered through Celite. The filtrate was washed with 2 N hydrochloric acid (2xc3x9725 mL) followed by 2 N sodium hydroxide (25 mL). The organic layer was concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with 5% EtOAc/Hexane to provide 0.85 g (76%) of the title compound as an orange solid.
MS (EI, m/z) C12H13N (M+)=171.4
Beginning with 4,5,6,7-tetrahydroazepino[3,2,1-hi]indole, the title compound was prepared essentially as described in Preparation V.
MS (FIA, m/z) C15H15NO3 (M++1)=258.2
Beginning with indole-7-carboxaldehyde and ethanolamine, the title compound was prepared essentially as described in Preparation IV.
MS (IS, m/z) C16H20N2O2 (M++1)=273
Beginning with S-6-(tert-butoxycarbonyl)-5,6-dihydro-6H-[1,4]diazepino[6,7,1-hi]indole, the title compound was prepared essentially as described in Preparation V.
MS (IS, m/z) C16H20N2O2 (M++1)=273
7-Vinyl-1H-indole
To 7-bromo-1H-indole (6.0 g, 30.6 mmol) in 150 mL of dimethylformamide was added tributyl(vinyl)tin (9.8 mL, 33.7 mmol), triphenylphosphine (0.4 g, 1.53 mmol), diphenyl-palladium(II) dichloride (1.07 g, 1.53 mmol) and lithium chloride (4.0 g, 94.4 mmol), and the resulting mixture was heated at 100xc2x0 C. overnight. The reaction mixture was cooled to 20-24xc2x0 C. and poured into 150 mL of water and 150 mL of ethyl acetate. The aqueous layer was washed with additional ethyl acetate (3xc3x97100 mL) and the combined organic layers were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 5-10% ethyl acetate in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 3.5 g (80%) of the desired compound as a clear oil.
MS (FIA, m/z) C10H9N (M++1)=144.2
1-(Pent-4-en-1-yl)-7-vinyl-1H-indole
To a 0xc2x0 C. solution of 7-vinylindole (5.0 g, 34.9 mmol) in 140 mL of dimethylformamide was added sodium hydride (60% dispersion in mineral oil) (3.5 g, 87.3 mmol). The ice bath was removed and the solution was warmed to 20-24xc2x0 C. and stirred an additional 30 minutes. 5-Bromo-1-pentene (20 mL, 175 mmol) was added dropwise and stirring continued for 3 hrs. The solution was poured into 150 mL of water and 150 mL of ethyl acetate. The aqueous layer was washed with additional ethyl acetate (3xc3x97100 mL) and the combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 5-10% ethyl acetate in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 5.39 g (73%) of the desired compound as a clear oil.
MS (ES, m/z) C15H17N (M++1)=212
Ring Closure
To a solution of 1-(Pent-4-en-1-yl)-7-vinyl-1H-indole (4.4 g, 20.8 mmol) in anhydrous dichloromethane (3.0 L) was added 1.4 g of bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride (Grubb""s catalyst). The resulting solution was stirred at 20-24xc2x0 C. for 24 hours. An additional 1.0 g of Grubb""s catalyst was added to the reaction and the solution was stirred for 4 hours. The reaction was then concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with 2-5% ethyl acetate in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 3.0 g (79%) of the title compound as a brown oil.
1H NMR (400 MHz, DMSO-d6) xcex47.41-7.39 (dd, 1H, J=7.81, 0.98 Hz), 7.22-7.21 (d, 1H, J=3.42 Hz), 6.94-6.9 (d, 1H, J=7.57 Hz), 6.81-6.8 (d, 1H, J=2.93 Hz), 6.79 (s, 1H), 6.36-6.35 (d, 1H, J=2.93 Hz), 5.69-5.62 (m, 1H), 4.45-4.3 (bs, 2H), 2.19-2.14 (m, 2H), 1.75-1.55 (bs, 2H).
Beginning with 8,9-Dehydropyrrolo[3,2,1-kl]benzo[b]azacyclooctane, the title compound was prepared essentially as described in Preparation V.
1H NMR (400 MHz, DMSO-d6) xcex48.44 (S, 1H), 8.13-8.11 (dd, 1H, J=7.81, 0.98 Hz), 7.26-7.22 (t, 1H, J=7.81 Hz), 7.06-7.04 (d, 1H, J=7.33 Hz), 6.86-6.84 (d, 1H, J=11.2 Hz), 5.84-5.74 (m, 1H), 4.6-4.4 (bs, 4H), 3.87 (s, 3H), 2.25-2.0 (bs, 2H)
A solution of 8,9-Dehydropyrrolo[3,2,1-kl]benzo[b]azacyclooctane (0.66 g, 3.6 mmol) in ethanol (130 mL) was hydrogenated in the presence of platinum oxide (100 mg) under balloon pressure for three hours. The mixture was filtered through Celite using dichloromethane and the filtrate was concentrated under reduced pressure to provide 0.65 g (97%) of the title compound as a light yellow oil.
MS (ES, m/z) C13H15N (M++1)=186
Beginning with pyrrolo[3,2,1-kl]benzo[b]azacyclooctane, the title compound was prepared essentially as described in Preparation V.
1H NMR (400 MHz, DMSO-d6) xcex48.38 (s, 1H), 8.05-8.03 (d, 1H, J=7.81 Hz), 7.18-7.15 (t, 1H, J=7.57 Hz), 7.03-7.01 (d, 1H, J=6.84 Hz), 4.65-4.62 (t, 2H, J=6.1 Hz), 3.86 (s, 3H), 3.3-3.15 (bs, 2H), 1.94-1.91 (t, 2H, J=6.1 Hz), 1.82-1.79 (t, 2H, J=5.86 Hz), 1.3-1.15 (bs, 2H).
N-Allyl N-[(1H-indol-7-yl)methyl]amine
To a solution of indole-7-carboxaldehyde 1 (4.00 g, 27.6 mmol) in 1,2-dichloroethane (120 mL) at 20-24xc2x0 C. was added allylamine (2.50 mL, 33.1 mmol), acetic acid (3.4 mL), and sodium triacetoxyborohydride (5.85 g, 27.6 mmol). The resulting mixture was stirred at 20-24xc2x0 C. for 5 hours. An additional 1.5 g (7.1 mmol) of sodium triacetoxyborohydride was added and the resulting mixture was stirred overnight. The mixture was diluted with dichloromethane (300 mL), washed carefully with aqueous sodium bicarbonate (100 mL), and the layers were separated. The organic layer was washed with water (100 mL), saturated aqueous sodium chloride (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 10-30% ethyl acetate in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 4.21 g (82%) of the desired compound as a light yellow oil.
N-[tert-butoxycarbonyl]N-allyl N-[(1H-indol-7-yl)methyl]amine
To a 0xc2x0 C. solution of N-allyl N-[(1H-indol-7-yl)methyl]amine (4.21 g, 22.6 mmol) in anhydrous tetrahydrofuran (100 mL) was added a 0xc2x0 C. solution of di-tert-butyl dicarbonate (4.93 g, 22.6 mmol) in anhydrous tetrahydrofuran (20 mL). The resulting solution was stirred for two hours and allowed to warm to 20-24xc2x0 C. The reaction mixture was diluted with ethyl acetate (500 mL). The phases were separated and the organic layer was washed with water (2xc3x97150 mL), saturated aqueous sodium chloride (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 6.5 g (100%) of the desired compound as a light yellow oil.
1H NMR (400 MHz, DMSO-d6) xcex411.08-10.65 (m, 1H), 7.5-7.4 (m, 1H), 7.38-7.3 (bs, 1H), 6.97-6.94 (t, 1H, J=7.32 Hz), 6.92-6.8 (bs, 1H), 6.45-6.4 (m, 1H), 5.8-5.65 (m, 1H), 5.1-5.0 (m, 2H), 4.59 (s, 2H), 3.85-3.68 (m, 2H), 1.5-1.2 (m, 9H)
MS (ES, M/z) C17H22N2O2 (M++1)=287.2
N-[tert-butoxycarbonyl]N-allyl N-[(1-allyl-1H-indol-7-yl)methyl]amine
To a 0xc2x0 C. solution of N-[tert-butoxycarbonyl]N-allyl N-[(1H-indol-7-yl)methyl]amine (6.6 g, 23 mmol) in anhydrous dimethylformamide was added slowly sodium hydride (60% dispersion in mineral oil, 1.75 g, 43.7 mmol). The mixture was warmed to 20-24xc2x0 C. and stirred for 30 minutes, followed by the addition of allyl bromide (4.0 mL, 46 mmol). The reaction was then stirred at 20-24xc2x0 C. overnight. The reaction mixture was diluted with ethyl acetate (450 mL), washed with water (2xc3x97100 mL), saturated aqueous sodium chloride (150 mL), and the organic layer dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 10% ethyl acetate in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 6.8 g (91%) of the desired compound as a light brown oil.
MS (ES, m/z) C20H26N2O2 (M++Na)=349.2
Ring Closure
Beginning with N-[tert-butoxycarbonyl]N-allyl N-[(1-allyl-1H-indol-7-yl)methyl]amine, the ring closure was performed essentially as described in Preparation XIV.
MS (ES, M/z) C18H22N2O2 (M++Na)=321.2
Reduction
Beginning with the alkene prepared in the previous paragraph, the double bond was reduced to provide the title compound essentially as described in Preparation XVI.
MS (ES, m/z) C18H25N2O2 (M+)=301.2
Beginning with 8-(tert-butoxycarbonyl)-[1,5]diazaperhydroonino[8,9,1-hi]indole, the title compound was prepared essentially as described in Preparation V.
MS (IS, m/z) C21H26N2O5 (M++1)=387.
Beginning with 6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydroquinoline (Bioorg. Med. Chem. Lett. 1335-1340 (1999)), the title compound was prepared as described in Preparation I.
MS(ES): m/e=204.2 (M+1)
Beginning with (N-[tert-butoxycarbonyl]N-[methyl]7-aminomethylindol-3-yl)oxoacetic acid methyl ester and (6-fluoroindol-3-yl)acetamide, the title compound was prepared essentially as described in Preparation XX.
MS(m/z): 421.1 (M+xe2x88x921)
Beginning with indole-7-carboxaldehyde and lysine methyl ester, the title compound was prepared essentially as described in Preparation IV.
MS(m/z): 458.0 (M++1)
Beginning with S-6-(tert-butoxycarbonyl)-5-(N-[tert-butoxycarbonyl]N-[methyl]4-aminobut-1-yl)-5,6-dihydro-6H-[1,4]diazepino[6,7,1-hi]indole, the title compound was prepared essentially as described in Preparation V.
MS(m/z): 544.0 (M++1)
S-4-benzyloxycarbonylamino-5-hydroxy-pentanoic acid tert-butyl ester
To a solution of N-[benzyloxycarbonyl]-L-glutamic acid xcex3-tert-butyl ester (3.37 g, 10.0 mmol) in 1,2-dimethoxy ethane (10 ml) at xe2x88x9215xc2x0 C. under nitrogen was added N-methyl-morpholine (1.11 ml, 10 mmol) and isobutyl chloroformate (1.36 ml, 10 mmol). The resulting suspension was immediately filtered and washed with 1,2-dimethoxyethane. To the filtrate was added a solution of sodium borohydride (0-57 g, 15.0 mmol) in water (5 ml) and then water (250 ml) was added. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3.08 g (95%) of the desired compound as an oil.
MS (ES, m/z) (M+1)=324.0, (Mxe2x88x921)=321.9.
N-Deprotection
A solution of S-4-(Benzyloxycarbonyl)amino-5-hydroxy-pentanoic acid tert-butyl ester (5.13 g, 15.9 mmol) in methanol (50 ml) was added to a suspension of Pd/C (1.69 g, 10%) in methanol (50 ml) and the mixture was stirred under a hydrogen atmosphere for 6 h. The catalyst was carefully filtered off and the filtrate was concentrated under reduced pressure to provide 2.95 g (98%) of the title compound as a white solid.
MS (ES, m/z) (M+1)=189.9
Beginning with indole-7-carboxaldehyde and S-4-amino-5-hydroxypentanoic acid tert-butyl ester, the title compound was prepared essentially as described in Preparation IV.
MS (ES, m/z), (M+1)=401.0
Beginning with S-6-(tert-butoxycarbonyl)-5-(2-(tert-butoxycarbonyl)eth-1-yl)-5,6-dihydro-6H-[1,4]diazepino-[6,7,1-hi]indole, the title compound was prepared essentially as described in Preparation V.
MS (ES, m/z) (M+1)=487.0
To a solution of 5-hydroxy-4-[(1H-indol-7-ylmethyl)-amino]pentanoic acid tert-butyl ester (3.60 g, 11.3 mmol) in tetrahydrofuran (100 ml) was added triethylamine (4.72 ml, 33.9 mmol) and N-[benzyloxycarbonyl]succinimide (2.54 g, 10.2 mmol) under nitrogen. Following 2 hours of stirring at room temperature the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with ethyl acetate:hexanes (1:1). Fractions containing product were combined and concentrated under reduced pressure to provide 3.96 g (86%) of the title compound as an oil.
MS (ES, m/z) 451.0 (Mxe2x88x921)
Beginning with N-[benzyloxycarbonyl]N-[(indol-7-yl)methyl]-5-hydroxypentanoic acid tert-butyl ester, the title compound was prepared essentially as described in Preparation IV.
1H NMR (400 MHz, CDCl3) xcex47.43 (m, 1H), 7.23 (m, 3H), 7.05-6.90 (m, 5H), 6.40 (m, 1H), 5.10-4.60 (m, 4H), 4.40-4.10 (m, 3H), 2.20 (m, 2H), 1.90 (m, 2H), 1.46 (s, 9H).
Beginning with S-6-(benzyloxycarbonyl)-5-(2-(tert-butoxycarbonyl)eth-1-yl)-5,6-dihydro-6H-[1,4]diazepino-[6,7,1-hi]indole, the title compound was prepared essentially as described in Preparation V.
MS (ES, m/z) 520.9 (M+1).
3,4-Dihydro-2H-benzo[1,4]Thiazine.
A solution of (2H)1,4-benzothiazin-3(4H)-one (20.0 g, 121.1 mmol) in anhydrous tetrahydrofuran (100 mL) was added to a stirred suspension of lithium aluminum hydride in anhydrous tetrahydrofuran (80 mL) under nitrogen at 0xc2x0 C. The mixture was heated at reflux for 2 hrs and then poured into a mixture of ethyl acetate (300 mL) and ice (500 g). The organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic layer was dried and concentrated under reduced pressure to provide 17.68 g (96.5%) of the desired compound which was used without further purification.
IS-MS, m/e 151.9 (m+1)
Ring Formation/Decarboxylation
Beginning with 3,4-dihydro-2H-benzo[1,4]thiazine, the title compound was prepared essentially as described in Preparation I.
IS-MS, m/e 175.9 (m+1).
Beginning with 3,4-dihydro-5-thia-2a-aza-acenaphthylene, the title compound was prepared essentially as described in Preparation II.
IS-MS, m/e 261.9 (m+1)
N-[3,3-dimethylpropyn-3-yl]aniline
A mixture of aniline (21.8 g, 234 mmol) and triethylamine (26.6 g, 263.3 mmol) in 100 mL ether, 25 mL water, 0.2 g copper(I) chloride and 0.2 g copper bronze was prepared under nitrogen in a three-neck flask equipped with mechanical stirrer. 3-Chloro-3-methyl-1-butyne (20 g, 195 mmol) in ether (25 mL) was slowly added with stirring while maintaining an inside temperature at 10-20xc2x0 C. After stirring for an additional 2 hours at room temperature, the mixture was poured into a mixture of 200 mL ether and 100 mL water. The ethereal layer was washed with cold water, dried for 15 minutes over anhydrous potassium carbonate and filtered, redried with potassium hydroxide pellets overnight. The solution was filtered and concentrated under reduced pressure.
1,2-Dihydro-2,2-dimethylquinoline
A mixture of N-[3,3-dimethylpropyn-3-yl]aniline and cuprous chloride (3.9 g) in toluene (140 mL) was refluxed under nitrogen for 4xc2xd hrs. The reaction mixture was filtered and the filtrate washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with dichloromethane:hexane (1:1) to provide the desired compound.
Reduction
1,2-Dihydro-2,2-dimethylquinoline (13.69 g, 86.0 mmol) was hydrogenated over 5% platinum on carbon (12.5 g) in ethyl acetate (500 mL) at room temperature and 60 PSI to give 12.8 g (92.4% yield) of the title compound.
IS-MS, m/e 162.0 (m+1)
A degassed solution of 6-bromoindole (1.0 g, 5.1 mmol), 4-fluorobenzeneboronic acid (0.928 g, 6.63 mmol), potassium phosphate (2.7 g, 153 mmol) and palladium(0)tetrakis-(triphenylphosphine) (0.294 g, 0.255 mmol) in dimethylacetamide (50 mL) was heated at 120xc2x0 C. for 14 hours. After cooling to room temperature, the mixture was diluted with water. The suspension was filtered, the solid washed with water and then dissolved in ethyl acetate (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with ethyl acetate:hexane (1:4) to give 0.411 g (38.2%) of the title compound as a white crystalline solid.
IS-MS, m/e 209.9 (mxe2x88x921)
Beginning with 6-(4-fluorophenyl)indole, the title compound was prepared essentially as described in Preparation II.
IS-MS, m/e 295.9 (mxe2x88x921).
Beginning with 6-bromoindole and pyridine-3-boronic acid, the title compound was prepared essentially as described in Preparation XXXIII and XXXIV.
IS-MS, m/e 278.9 (mxe2x88x921).
Pyrrolo[3,2,1-hi]indole-2-carboxylic acid, 4,5-dihydro-, ethyl ester
To a solution of N-amino-indoline (Wijngaarden, Ineke van, et al., J. Med. Chem., 36, 3693 (1993)) (1.0 g, 7.45 mmol) in 15 mL absolute ethanol was added ethyl pyruvate (0.88 ml, 7.88 mmol) and the mixture was heated to reflux under nitrogen for one hour. After cooling, the solvents were removed under reduced pressure to give 1.61 g (93%) of the crude product as a tan solid. The crude imine (0.5 g, 2.15 mmol) was dissolved in 5 mL of glacial acetic acid and treated with boron trifluoride etherate (0.28 mL, 2.21 mmol). The reaction mixture was heated at reflux for 45 minutes, cooled and poured into 25 mL ice-water. Extraction with ethyl acetate (2xc3x9725 mL) was followed by washing of the combined organic layers with saturated aqueous sodium bicarbonate (1xc3x9720 mL), water (1xc3x9720 mL) and saturated aqueous sodium chloride (1xc3x9710 mL). After drying over sodium sulfate, the ethyl acetate extracts were filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane and filtered through a plug of flash silica gel, washing with 15 mL of 2% methanol in dichloromethane. Concentration under reduced pressure gave the product in 19% yield as a yellow solid.
MS (EI, m/z) C13H13N1O2 (M+)=215.
4,5-dihydro-pyrrolo[3,2,1-hi]indole-2-carboxylic acid
To a solution of the ester (2.2 g, 10.2 mmol) in 50 mL of ethanol was added 50 mL of 1N aqueous sodium hydroxide and the mixture was heated at reflux for 40 minutes. After cooling in an ice-bath, the reaction was neutralized with 50 mL of 1N hydrochloric acid and extracted with dichloromethane (3xc3x9750 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the product (1.78 g, 94%) as a yellow solid. MS (EI, m/z) C11H9N1O2 (M+, M+xe2x88x92CO2H)=187, 142.
Decarboxylation
A solution of the carboxylic acid (1.5 g, 8.0 mmol) and copper(II) oxide (2.5 g, 31.4 mmol) in 40 mL of quinoline was heated to 200xc2x0 C. for 90 minutes. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (300 mL), filtered through Celite and washed with 2.0 M hydrochloric acid (3xc3x9750 mL), water (1xc3x9750 mL) and saturated aqueous sodium chloride (1xc3x9750 mL). The organic layer was filtered through a pad of flash silica gel and evaporated to 1.5 g of a dark oil. Chromatography (1-3% ethyl acetate in hexanes) gave 4,5-dihydro-pyrrolo[3,2,1-hi]indole (0.364 g) in 33% yield as a tan solid.
MS (IS, m/z) C10H9N1 (M++1)=144.
Also isolated was 0.245 g of pyrrolo[3,2,1hi]indole as a white solid.
MS (EI, m/z) C10H7N1 (M+, M++1)=141, 142.
Beginning with 4,5-dihydropyrrolo[3,2,1-hi]indole, the title compound was prepared essentially as described in Preparation II.
MS (IS, m/z) C13H11N1O3 (M++1, M++2)=230, 231.
(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetamide
To a solution of (5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester (0.50 g, 2.06 mmol) in 10 mL of tetrahydrofuran at 0xc2x0 C. was added concentrated ammonium hydroxide (2 mL). The bath was removed and the mixture stirred 3 hours. After diluting with 20 mL of water, the suspension was filtered, washed with 10 mL of water followed by 10 mL of diethyl ether, and dried under reduced pressure to provide 0.403 g (86%) of the desired compound as a light yellow solid.
MS (IS, m/z) C13H12N2O2 (M++1)=229
Reduction
To a solution of (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide (0.30 g, 1.31 mmol) in dioxane (6 mL) and water (2 mL) was added 10% palladium on carbon (0.060 g), followed by the careful addition of NaH2PO2.H2O (0.60 g, 5.67 mmol) and the reaction was brought to reflux under nitrogen. After 3 hours an additional 0.60 g of NaH2PO2.H2O was added and the reaction was heated at reflux for another 6 hrs. The mixture was cooled, filtered through a pad of Celite, and washed well with ethyl acetate (100 mL). The solution was concentrated under reduced pressure and the residue triturated with water (20 mL). The resulting suspension was filtered and the recovered solid dried under reduced pressure to provide 0.27 g (96%) of the title compound as a white solid.
MS (IS, m/z) C13H14N2O1 (M++1)=215
(6,6-Dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetic acid
To a solution of glacial acetic acid (80 mL) and concentrated hydrochloric acid (9 mL) was added 3,4-dihydro-4,4-dimethyl-1-(2H)-quinolinamine (9.5 g, 53.9 mmol) and 2-ketoglutaric acid (9.7 g, 65.1 mmol) and the suspension heated at reflux for 3 hours. After cooling the solvents were removed under reduced pressure and the residue dissolved in 500 mL of ethyl acetate. The ethyl acetate solution was washed with water (3xc3x97150 mL) and saturated aqueous sodium chloride (1xc3x9750 mL), dried over sodium sulfate,-filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 1-4% methanol in dichloromethane. Fractions containing product were combined and concentrated under reduced pressure to provide 4.45 g (34%) of the desired compound as a tan foam. An impure fraction was extracted with 1N sodium hydroxice (2xc3x9750 mL) and the combined aqueous layers washed with diethyl ether (20 mL) and made acidic with concentrated hydrochloric acid (8 mL). This aqueous mixture was extracted with dichloromethane (2xc3x97100 mL), followed by drying (Na2SO4) to provide an additional 2.55 g (19%) of desired product
MS (IS, m/z) C15H17N1O2 (M++1)=244
Amide Formation
To a solution of (6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetic acid (5.7 g, 23.4 mmol) in 100 mL of dry tetrahydrofuran at 0xc2x0 C. was added N-methylmorpholine (2.9 mL, 26.1 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 4.5 g, 24.9 mmol) and the reaction mixture allowed to come to room temperature overnight. After cooling to 0xc2x0 C., another 4.5 g of CDMT was added and stirring was continued at room temperature for another 2 hours. The solution of activated ester was cooled to xe2x88x9230xc2x0 C. and 25 mL of ammonia was condensed directly into the flask. After stirring at xe2x88x9230xc2x0 C. for 1 hour, the reaction was allowed to come to room temperature. The resulting suspension was filtered, and the recovered solid rinsed with 250 mL of tetrahydrofuran. The filtrate was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (500 mL) and water (100 mL). The organic phase was washed with 0.1 N sodium hydroxide (1xc3x97100 mL), water (1xc3x97100 mL) and saturated aqueous sodium chloride (1xc3x9750 mL), dried over sodium sulfate and filtered through a 1-inch pad of flash silica gel. The filtrate was concentrated under reduced pressure and the resulting solid was slurried with 50 mL of diethyl ether, filtered and dried under reduced pressure to provide 3.3 g (58%) of the title compound as an off-white solid.
MS (IS, m/z) C15H18N2O1 (M++1)=243.
Beginning with 2-(8-fluoro-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Preparation XXXVII.
MS (IS, m/z) C15H17FN2O (M++1)=261
Beginning with 5-phenoxyindole, the title compound was prepared essentially as described in Preparation II.
MS (IS, m/z) C17H13NO4 (M+xe2x88x921)=294
Beginning with 5,6-difluoroindole, the title compound was prepared essentially as described in Preparations II and XXXVII.
MS (IS, m/z) C10H8F2N2O (M++1)=211
Beginning with 5-benzyloxyindole, the title compound was prepared essentially as described in Preparation II.
MS (IS, M/z) C18H15NO4 (M++1)=310.
To a solution of 7-(2-hydroxyethyl)indole (2.86 g, 17.7 mmol) in 25 mL of dry dimethylformamide was added imidazole (2.54 g, 37.3 mmol) followed by triisopropylsilyl chloride (4.35 mL, 19.7 mmol) and the mixture stirred at room temperature under nitrogen for 3 hours. After diluting with hexanes (500 mL) the organic layer was washed with water (2xc3x9750 mL) and saturated aqueous sodium chloride (1xc3x9750 mL) and dried over magnesium sulfate. The mixture was filtered and concentrated under reduced pressure to provide 7-(2-(triisopropylsilyloxy)eth-1-yl)indole. This indole was reacted essentially as described in Preparation II to provide the title compound as a yellow solid.
MS (IS, m/z) C22H33NO4Si (M++1)=404
7-vinylindole
To a solution of methyl triphenylphosphonium bromide (5.05 g, 14.1 mmol) in tetrahydrofuran (80 mL) was added potassium tert-butoxide (1 M in tetrahydrofuran, 14.1 mL, 14.1 mmol) and the reaction stirred for 45 minutes at room temperature. Next a prepared solution of 7-formylindole (1.00 g, 6.89 mmol) in tetrahydrofuran (10 mL) was added and the reaction stirred for 1.5 hours. The reaction mixture was diluted with ethyl acetate (250 mL) and washed with an 8:1 mixture of water and 1 N hydrochloric acid (2xc3x97100 mL), saturated aqueous sodium chloride (100 mL), and dried over sodium sulfate. The solution was filtered and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography. Fractions containing product were combined and concentrated under reduced pressure to provide the desired compound as a brown oil.
MS (IS, m/z) C10H9N (M++1)=144
Hydroboration/Oxidation
To a 0xc2x0 C. solution of 7-vinylindole 1 (0.95 g, 6.6 mmol) in anhydrous tetrahydrofuran (60 mL) was added 1 M borane-tetrahydrofuran complex in tetrahydrofuran (9.95 mL, 9.95 mmol) and the reaction stirred overnight at room temperature. 1 N sodium hydroxide (25 mL) and 30% hydrogen peroxide (35 mL) were then added and the mixture stirred at reflux for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (50 mL) and saturated aqueous sodium chloride (2xc3x9750 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 50% ethyl acetate in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 0.60 g (56%) of the desired compound as a yellow oil.
MS (IS, m/z) C10H11NO (M++1)=162.
Alcohol Activation
A solution of 7-(2-hydroxyeth-1-yl)indole (0.54 g, 3.34 mmol) and triethylamine (2.3 mL, 16.7 mmol) in dichloromethane (45 mL) was stirred at 0xc2x0 C. To this was added a prepared solution of methanesulfonyl chloride (0.29 mL, 3.68 mmol) in dichloromethane (5 mL) dropwise over 30 minutes and the reaction was stirred for an additional 2 hours at room temperature. Upon completion the reaction was diluted with dichloromethane (50 mL) and washed with water (30 mL) and saturated aqueous sodium chloride (2xc3x9730 mL) and dried over sodium sulfate. The drying agent was then filtered and the filtrate was concentrated under reduced pressure.
Nucleophilic Displacement
To a solution of 7-(2-(methanesulfonyloxy)eth-1-yl)indole (0.79 g, 3.3 mmol) in ethanol (50 mL) was added ethanolamine (5 mL, 82 mmol) and the reaction stirred at reflux overnight. The reaction was diluted with ethyl acetate (150 mL) and washed with water (3xc3x9750 mL), saturated aqueous sodium chloride (2xc3x9750 mL) and dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 0.57 g (85%) 7-(2-(N-[2-hydroxyeth-1-yl]amino)eth-1-yl)indole as a light-brown solid.
MS (IS, m/z) C12H16N2O (M++1)=205
Ring Formation
Beginning with 7-(2-(N-[2-hydroxyeth-1-yl]amino)eth-1-yl)indole, the title compound was prepared essentially as described in Preparation IV.
MS (IS, m/z) C17H22N2O2 (M++1)=287
Beginning with 6-(tert-butoxycarbonyl)-5,6-dihydro-6H-[1,4]homodiazepino[6,7,1-hi]indole, the title compound was prepared essentially as described in Preparation II.
MS (IS, m/z) C20H24N2O5 (M++1)=373
Indole-6-carboxylic Acid Methyl Ester
To a solution of indole-6-carboxylic acid (39.5 g, 245 mmol) in methanol (200 mL) and dichloromethane (750 mL) was added 2 M (trimethylsilyl)diazomethane in hexanes (160 mL, 320 mmol) dropwise over 1 hour. The reaction was stirred at room temperature overnight. The following day the reaction was concentrated to a thick brown crude oil that was diluted with ethyl acetate (500 mL) and washed with saturated aqueous sodium bicarbonate (2xc3x97200 mL), saturated aqueous sodium chloride (2xc3x97200 mL) and dried over sodium sulfate. The mixture was then filtered and the filtrate concentrated under reduced pressure to form a suspension. The suspension was filtered to provide 43 g of the desired compound as an off-white solid.
6-(hydroxymethyl)indole
To a solution of indole-6-carboxylic acid methyl ester (20.0 g, 114 mmol) in anhydrous tetrahydrofuran (1.6 L) stirring under nitrogen at room temperature was added carefully lithium aluminum hydride (8.7 g, 230 mmol) while purging with nitrogen. Following this addition, the reaction mixture was stirred at room temperature for 3 hours and was then cooled to 0xc2x0 C. This mixture was treated sequentially with water (9 mL), 15% sodium hydroxide (9 mL), and additional water (25 mL). The resulting suspension was filtered and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 30%-60% ethyl acetate in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 16.0 g (95%) of the desired compound as an off-white solid.
IS-MS, m/e 146.0 (mxe2x88x921).
Silylation
To a solution of 6-(hydroxymethyl)indole (16.0 g, 110 mmol) in dichloromethane (800 mL) stirring at 0xc2x0 C. under nitrogen was added triethylamine (22.5 mL, 160 mmol). Next a prepared solution of triisopropylsilyl trifluoromethanesulfonate (30.5 mL, 115 mmol) in dichloromethane (200 mL) was added slowly using an addition funnel. The reaction was stirred at 0xc2x0 C. for 3 hours. The reaction was then diluted with dichlormethane (200 mL) and washed with water (2xc3x97200 mL), saturated aqueous sodium chloride (2xc3x97200 mL) and dried over sodium sulfate. The solution was filtered and the filtrate concentrated under reduced pressure. The residue was sujected to silica gel chromatography. Fractions containing product were combined and concentrated under reduced pressure to provide the title compound.
IS-MS, m/e 302 (mxe2x88x921).
Beginning with 6-((triisopropylsilyloxy)methyl)indole, the title compound was prepared essentially as described in Preparation II.
IS-MS, m/e 388 (mxe2x88x921)
5-Chloro-1,2,3,4-tetrahydroquinoline
A mixture of 5-chloroquinoline (10.0 g) and platinum oxide (50 mg) in acetic acid was shaken under a hydrogen atmosphere at room temperature for 4 hours. The mixture was diluted with diethyl ether and filtered through Celite. The volatiles were removed under reduced pressure and the residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate (3xc3x97300 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified over silica gel and the fractions containing product were combined and concentrated under reduced pressure to provide 7.0 g (69%) of the desired compound.
MS (EI m/z) C9H10ClN (M+1)
Ring Formation/Decarboxylation
Beginning with 5-chloro-1,2,3,4-tetrahydroquinoline, the title compound was prepared essentially as described in Preparation I.
MS (EI m/z) C11H10ClN (M+) 192.1
Analysis for C11H10ClN:
Beginning with 9-chloro-5,6-dihydro-4H-pyrrolo-[3,2,1-ij]quinoline, the title compound was prepared essentially as described in Preparation II.
MS (IS m/z) C14H12ClNO3 (M+1) 278
Analysis for C14H12ClNO3:
Beginning with 6-chloroquinoline, the title compound was prepared essentially as described in Preparation XLVIII.
MS (IS, m/z) C11H10ClN (M+) 191.9
Beginning with 8-chloro-5,6-dihydro-4H-pyrrolo-[3,2,1-ij]quinoline, the title compound was prepared essentially as described in Preparation II.
MS (IS, m/z) C14H12ClNO3 (M+1) 277.8
Analysis for C14H12ClNO3:
5-fluoroquinoline
To a suspension of 5-aminoquinoline (50 g, 347 mmol) in 48% HBF4 (200 mL) at 0xc2x0 C. was added portionwise sodium nitrite. This was stirred for 1 hour and then poured into 1:1 ethyl acetate/diethyl ether (500 mL). The resulting suspension was filtered and the solid dried. This solid (82.5 g, 338 mmol) was added portionwise to refluxing xylene (1 L) and stirred for 2 hours then allowed to cool. The xylene was decanted off and the residue dissolved in 1N hydrochloric acid (600 mL). After neutralization with sodium carbonate, the mixture was extracted with ethyl acetate (10xc3x97500 mL). The extracts were dried over sodium sulfate, filtered and the volatiles removed under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 10-20% diethyl ether in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 28.1 g (55%) of the desired compound.
MS (EI, m/z) C9H6FN (M+1) 148.0
Reduction
A mixture of 5-fluoroquinoline (28.1 g), 5% palladium on carbon (5.6 g) in methanol was shaken over night at 40xc2x0 C. under 60 psi hydrogen. The mixture was filtered through celite and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 5-10% ethyl acetate in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 22.5 g (78%) of the title compound.
MS (EI, m/z) C9H10FN (M+1) 152.0
Beginning with 5-fluoro-1,2,3,4-tetrahydroquinoline, the title compound was prepared essentially as described in Preparation I.
MS (EI, m/z) C11H10FN (M+1) 176.1
Analysis for C11H10FN:
Beginning with 7-fluoro-5,6-dihydro-4H-pyrrolo-[3,2,1-ij]quinoline, the title compound was prepared essentially as described in Preparation II.
MS (EI, m/z) C14H12FNO3 (M+1) 262.1
Analysis for C14H12FNO3:
Beginning with 6-aminoquinoline, the title compound was prepared essentially as described in Preparation LIII.
MS (EI, m/z) C9H10FN (M+1) 152.0.
Beginning with 6-fluoro-1,2,3,4-tetrahydroquinoline, the title compound was prepared essentially as described in Preparation I.
MS (EI, m/z) C11H10FN (M+) 175.1
Analysis for C11H10FN:
Beginning with 8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline, the title compound was prepared essentially as described in Preparation II.
MS (El, m/z) C14H12FNO3 (M+1) 262.1
Analysis for C14H12FNO3:
Indole-6-carboxaldehyde
To a solution of 6-cyanoindole (15.0 g) and sodium hypophosphite (90 g) in water (326 mL), acetic acid (326 mL), and pyridine (652 mL) was added Raney Nickel catalyst and the mixture stirred at 45xc2x0 C. for 45 minutes. The mixture was filtered through Celite and the filtrate extracted with ethyl acetate (3xc3x97500 mL). The extracts were dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was crystallized from a mixture of dichloromethane and hexanes to provide 13.6 g (89%) of the title compound.
MS (EI, m/z) C9H7NO (M+1) 145.9
6-(2-Nitrovinyl)-1H-indole
A mixture of indole-6-carboxaldehyde (2.8 g), nitromethane (30 mL) and ammonium acetate (0.560 g) was stirred at 100xc2x0 C. for 30 minutes. The excess nitromethane was removed under reduced pressure and the residue washed with water, dissolved in ethyl acetate (500 mL), dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to a volume of about 50 mL. This solution was then diluted with petroleum ether and the resulting suspension filtered and dried to provide 3.3 g (91%) of the desired compound.
MS (EI, m/z) C10H8N2O2 (Mxe2x88x921) 186.9
2-(1H-Indol-6-yl)Ethylamine
To a solution of 6-(2-Nitrovinyl)-1H-indole (1.0 g) in tetrahydrofuran (100 mL) was added portionwise lithium aluminum hydride (0.95 g) and the resulting mixture stirred at reflux for 1 hour. The reaction mixture was treated sequentially with water (0.95 mL), 15% sodium hydroxide (0.95 mL), and water (2.85 mL). The resulting suspension was filtered and the filtrate diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate (100 mL), saturated aqueous sodium chloride, dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography. Fractions containing product were combined and concentrated under reduced pressure to provide 0.525 g (62%) of the desired compound.
MS (EI, m/z) C10H12N2 (M+1) 160.9
Nitrogen Protection
To a solution of 2-(1H-Indol-6-yl)ethylamine (0.50 g) in acetonitrile (25 mL) was added dimethylaminopyridine followed by di-tert-butyl dicarbonate (45 mg). After stirring at room temperature for 24 hours, the mixture was diluted with ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate (200 mL), water (2xc3x97200 mL), saturated aqueous sodium chloride, dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 20-40% ethyl acetate in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 0.42 g (52%) of the title compound.
MS (EI, m/z) C15H20N202 (Mxe2x88x921) 258.9
Beginning with N-[tert-butoxycarbonyl]2-(1H-indol-6-yl)ethylamine, the title compound was prepared essentially as described in Preparation II.
MS (EI, m/z) C18H22N2O5 (Mxe2x88x921) 345.1
4H-Pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester and 6H-Pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester
To a solution of 7-formylindole (30 g, 0.206 mol) in dimethylformamide (930 mL) was added cesium carbonate (148.2 g, 0.454 mol) and the mixture was stirred vigorously at room temperature for 30 min. Methyl 3-bromopropionate (51.6 g, 0.308 mol) was added and the reaction mixture was heated to 80xc2x0 C. for 24 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and filtered through a pad of Celite. The filtrate was washed with water and saturated aqueous sodium chloride, and the aqueous layers were back extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was passed through a short silica plug and concentrated under reduced pressure. Recrystallization of the crude product from chloroform and hexanes gave 4H-pyrrolo[3,2, 1-ij]quinoline-5-carboxylic acid methyl ester (17 g, 38.7% yield). Chromatography of the mother liquor gave additional 4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester (1.27 g, 2.9% yield) and 6H-Pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester (0.51 g, 1.2% yield).
4H-Pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester 1H NMR (CDCl3, 400 MHz) xcex43.82 (s, 3H), 5.27 (d, J=1.47 Hz, 2H), 6.45 (d, J=2.93 Hz, 1H), 6.89xcx9c6.93 (m, 2H), 7.05 (d, J=2.93 Hz, 1H), 7.45 (dd, J1=2.45 Hz, J2=6.36 Hz, 1H), 7.64 (t, J=1.95 Hz, 1H); MS (ES, m/z) C13H11NO2 212.2 (M++1).
6H-Pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester 1H NMR (CDCl3, 400 MHz) xcex43.73 (s, 3H), 3.94 (d, J=1.0 Hz, 2H), 6.38 (d, J=3.4 Hz, 1H), 6.88 (d, J=7.33 Hz, 1H), 6.92 (d, J=2.94 Hz, 1H), 7.02 (t, J=7.58 Hz, 1H), 7.21 (d, J=7.82 Hz, 1H), 7.73 (t, J=1.46 Hz, 1H)
5,6-dihydro-4H-Pyrrolo[3,2,1-ij]quinoline-5-carboxylic Acid Methyl Ester
4H-Pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester (10.9 g, 51.1 mmol) and palladium on carbon (5%, 1.1 g) were taken into tetrahydrofuran (300 mL), and the mixture was stirred under 60 psi of hydrogen at room temperature for 8 hours. Additional palladium on carbon (5%, 0.6 g) was added, and the mixture stirred under 60 psi of hydrogen for another 15 hours. Filtration and concentration of filtrate gave the desired compound.
Reduction
To a solution of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester (8.78 g, 40.8 mmol) in tetrahydrofuran (420 mL) at 0xc2x0 C. was added a solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 100 mL, 100 mmol) dropwise, and the mixture was allowed to warm to room temperature slowly. After stirring at room temperature for 2 hours, the reaction was quenched by water carefully. The mixture was passed through a short pad of Celite, and concentration of the filtrate gave the title compound.
MS (electrospray, m/z) C12H13NO: 188.1(M++1), 186.1(M+xe2x88x921).
To a solution of 5-(hydroxymethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (47 mmol) in dichloromethane (143 mL) at 0xc2x0 C. was added tert-butyldimethylsilyl chloride (7.63 g, 49.4 mmol), followed by triethylamine (7.92 mL, 56.4 mmol) and dimethylaminopyridine (0.58 g, 4.7 mmol). The reaction was allowed to warm to room temperature and stirred 2 hours. The reaction was quenched with water, extracted with dichloromethane and the combined organics dried over sodium sulfate. The organic phase was concentrated under reduced pressure to provide 5-(tert-butyldimethylsilyloxy-methyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline. This material was treated essentially as described in Preparation II to provide the title compounds.
(5-(tert-butyldimethylsilyloxymethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl]oxoacetic acid methyl ester: 1H NMR (400 MHz, CDCl3) xcex40.00 (s, 6H), 0.85 (s, 9H), 2.45xcx9c2.40 (m, 1H), 2.83xcx9c2.76 (m, 1H), 3.00xcx9c2.90 (m, 1H), 3.58xcx9c3.53 (m, 1H), 3.74 (dd, J1=4.9 Hz, J2=10.27 Hz, 1H), 3.89 (s, 3H), 4.01xcx9c3.95 (m, 1H), 4.30xcx9c4.27 (m, 1H), 7.01 (dd, J1=1.0 Hz, J2=7.33 Hz, 1H), 7.22xcx9c7.18 (m, 1H), 8.09 (d, J=8.31 Hz, 1H), 8.29 (s, 1H).
(5-Hydroxymethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester: MS (ES, m/z) C15H15NO4: 274.1 (M++1)
2-hydroxymethyl-1,2,3,4-tetrahydroquinoline
Sodium borohydride (21.7 g, 0.57 mol) was added in portions to a solution of quinoline-2-carboxaldehyde (30 g, 0.191 mol) in ethanol (300 mL) at 0xc2x0 C. The reaction mixture was warmed to room temperature, stirred at room temperature for 2 hrs, and quenched by water. Volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate, washed with water and saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography. Fractions containing product were combined and concentrated under reduced pressure to provide the desired compound and 2-(hydroxymethyl)quinoline. A solution of the recovered 2-(hydroxymethyl)quinoline in ethanol (250 mL) and tetrahydrofuran (250 mL) was hydrogenated at 60 psi in the presence of 5% platinum on carbon at 40xc2x0 C. for 48 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to provide the title compound.
1H NMR (400 MHz, CDCl3) xcex41.64xcx9c1.74 (m, 1H), 1.85xcx9c1.91 (m, 1H), 1.4xcx9c2.3 (br, 2H), 2.68xcx9c2.75 (m, 1H), 2.78xcx9c2.85 (m, 1H), 3.40xcx9c3.46 (m, 1H), 3.51xcx9c3.56 (m, 1H), 3.73 (dd, J1=3.91 Hz, J2=10.26 Hz, 1H), 6.51 (dd, J1=1.0 Hz, J2=7.83 Hz, 1H), 6.61 (dt, J1=1.0 Hz, J2=7.33 Hz, 1H), 6.93xcx9c6.98 (m, 2H).
Ring Formation/Decarboxylation
Beginning with 2-hydroxymethyl-1,2,3,4-tetrahydroquinoline, the title compound was prepared essentially as described in Preparation I.
MS (ES, m/z)188.1 (M++1), 186.1 (M+xe2x88x921)
Beginning with 4-hydroxymethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline, the title compounds were prepared essentially as described in Preparation LXI. (4-Hydroxymethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester: 1H NMR (400 MHz, CDCl3) xcex48.47 (s, 1H), 8.03 (d, J=7.81 Hz, 1H), 7.18 (t, J=7.33 Hz, 1H), 7.01 (d, J=6.84 Hz, 1H), 4.43xcx9c4.40 (m, 1H), 3.98xcx9c3.88 (m, 2H), 3.77 (s, 3H), 3.00xcx9c2.93 (m, 2H), 2.38 (br, 1H), 2.24xcx9c2.18 (m, 2H).
(4-(tert-butyldimethylsilyloxymethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl]oxoacetic acid methyl ester
1H NMR (400 MHz, CDCl3) xcex48.49 (s, 1H), 8.18 (d, J=7.33 Hz, 1H), 7.27 (t, J=7.58 Hz, 1H), 7.07 (dd, J1=1.0 Hz, J2=7.33 Hz, 1H), 4.44xcx9c4.41 (m, 1H), 3.94 (s, 3H), 3.92xcx9c3.82 (m, 2H), 3.01xcx9c2.98 (m, 2H), 2.26xcx9c2.23 (m, 2H), 0.89 (s, 9H), 0.00 (s, 6H).
4-(hydroxymethyl)-1,2,3,4-tetrahydroquinoline
Beginning with quinoline-4-carboxaldehyde, the desired compound was prepared essentially as described in Preparation LXII.
1H NMR (400 MHz, CDCl3) xcex41.85xcx9c2.00 (m, 2H), 2.82xcx9c2.90 (m, 1H), 3.15xcx9c3.26 (m, 2H), 3.66xcx9c3.75 (m, 2H), 6.43 (d, J=7.33 Hz, 1H), 6.55 (dt, J1=1.50 Hz, J2=7.33 Hz, 1H), 6.92 (dt, J1=1.50 Hz, J2=7.82 Hz, 1H), 6.98 (d, J=7.33 Hz, 1H)
4-(tert-Butyldiphenylsilyloxymethyl)-1,2,3,4-tetrahydroquinoline
To a solution of 4-(hydroxymethyl)-1,2,3,4-tetrahydroquinoline (16.07 g, 0.098 mol) in dichloromethane (100 mL) at 0xc2x0 C. were added sequentially triethylamine (16.3 mL, 0.12 mol), tert-butyldiphenylsilylchloride (28.4 g, 0.103 mol) and 4-(dimethylamino)pyridine (0.6 g, 4.9 mmol). After 30 minutes, the solution was warmed to room temperature and stirred for another 2 hours. The reaction mixture was diluted with dichlormethane (200 mL), washed with water (50 mL) and saturated aqueous sodium chloride solution (50 mL). The organic layers were collected, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to provide 22.1 g (56%) of the desired compound.
Ring Formation/Decarboxylation
Beginning with 4-(tert-butyldiphenylsilyloxy)-1,2,3,4-tetrahydroquinoline, the title compound was prepared essentially as described in Preparation I.
MS (ES, m/z) 426.1 (M++1)
Beginning with 6-(tert-butyldiphenylsilyloxymethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-I,j]quinoline, the title compound was prepared essentially as described in Preparation II.
MS (ES, m/z) 512.2 (M++1)
Beginning with indole-7-carboxaldehyde and methyl 4-bromobutyrate, the title compound was prepared essentially as described in Preparation LXI.
1H NMR (400 MHz, CDCl3) xcex41.78xcx9c1.82 (m, 1H), 2.10xcx9c2.30 (m, 2H), 2.90xcx9c3.00 (m, 1H), 3.10xcx9c3.20 (m, 1H), 3.57xcx9c3.60 (m, 2H), 3.94xcx9c4.05 (m, 1H), 4.30xcx9c4.40 (m, 1H), 6.36 (d, J=3.43 Hz, 1H), 6.87xcx9c6.93 (m, 3H), 7.38xcx9c7.40 (m, 1H)
Beginning with 6-(hydroxymethyl)-4,5,6,7-tetrahydroazepino[3,2,1-hi]indole, the title compound was prepared essentially as described in Preparation II.
MS (ES, m/z) C16H17NO4 288.1 (M++1), 286.2 (M+xe2x88x921)
Beginning with 3,3-dimethyl-1,2,3,4-tetrahydroquinoline (J. Chem. Soc. (Perkin I) 1635-1640 (1987)), the title compound was prepared as described in Preparation I.
Beginning with 5,5-dimethyl-4,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline, the title compound was prepared essentially as described in Preparation II.
MS(IS): m/e=272 (M+1)